Compositions, methods, and systems for the synthesis and use of imaging agents

ABSTRACT

The present invention relates to systems, compositions, and methods for the synthesis and use of imaging agents, or precursors thereof. An imaging agent precursor may be converted to an imaging agent using the methods described herein. In some cases, the imaging agent is enriched in  18 F. In some cases, an imaging agent may be used to image an area of interest in a subject, including, but not limited to, the heart, cardiovascular system, cardiac vessels, brain, and other organs. In some embodiments, methods and compositions for assessing perfusion and innervation mismatch in a portion of a subject are provided.

RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.14/343,627, filed Jun. 30, 2014, entitled “COMPOSITIONS, METHODS, ANDSYSTEMS FOR THE SYNTHESIS AND USE OF IMAGING AGENTS”, hereinincorporated by reference. U.S. application Ser. No. 14/343,627, filedJun. 30, 2014, is a U.S. National Stage application of InternationalPatent Application Serial No. PCT/US2012/054309, filed Sep. 7, 2012,entitled “COMPOSITIONS, METHODS, AND SYSTEMS FOR THE SYNTHESIS AND USEOF IMAGING AGENTS”, which claims priority under 35 U.S.C. §119(e) toU.S. Provisional Application Ser. No. 61/533,133, filed Sep. 9, 2011,entitled “COMPOSITIONS, METHODS, AND SYSTEMS FOR THE SYNTHESIS AND USEOF IMAGING AGENTS”; U.S. Provisional Application Ser. No. 61/656,489,filed Jun. 6, 2012, entitled “COMPOSITIONS, METHODS, AND SYSTEMS FOR THESYNTHESIS AND USE OF IMAGING AGENTS”; and U.S. Provisional ApplicationSer. No. 61/656,492, filed Jun. 6, 2012, entitled “METHODS ANDCOMPOSITIONS FOR ASSESSING PERFUSION AND INNERVATION MISMATCH”, theentire contents of each of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to compounds useful as imaging agents,compositions thereof, methods for the synthesis and use thereof, andprecursors thereto. In some embodiments, the compounds may be used toimage perfusion (e.g., cardiac perfusion). In other embodiments, thecompounds may be used to image innervation. The present invention alsoprovides methods and compositions for assessing perfusion andinnervation mismatch in a subject, for example, a human subject.

BACKGROUND OF THE INVENTION

Heart failure (HF) is defined as the inability of the heart to supplyperipheral organs with sufficient blood flow. It may be characterized bya hyperadrenergic state whereby increased systemic levels ofnorepinephrine (NE) and increased local spillover of catecholaminesoccur. The condition afflicts increasingly more people each year and isa common end-stage of many cardiac diseases and conditions includingmyocardial infarction, pressure/volume overload, viral myocarditis,toxic cardiomyopathy, valve failure, and other abnormalities. Theresultant myocardial damage, in conjunction with neurohormonal andcytokine activation, stimulates chamber remodeling which is the initialphase of heart failure. This remodeling process results in decreasedoverall myocardial efficiency and eventual progression to clinical HF.To date, however, no cure for the condition exists, thus early diagnosisis a key factor in its management and long-term prognosis. An imagingagent that identifies subjects in early HF would thus enable treatmentand life-style improvements for patients living with the condition.

Myocardial damage may also occur following tissue insult (e.g., amyocardial infarction), whereby innervation and perfusion defects mayform in a portion of the subject (i.e. a portion of the heart). Incertain cases, the size of the defect areas, as detected by imaging,could be different (e.g., regional mismatch) and may be associated withan increased probability for cardiac arrhythmia as well as otherconditions.

Accordingly, improved compositions, methods, systems, and apparatusesare needed for the synthesis and administration of imaging agents (e.g.,for imaging the heart).

SUMMARY OF THE INVENTION

The present invention provides, in a broad sense, compounds andcompositions thereof (including salt forms) that are useful as imagingagents or imaging agent precursors, methods of use thereof, and methodsfor synthesizing provided compounds. In some embodiments, the imagingagents may be used for imaging perfusion. In some embodiments, theimaging agents may be used for imaging a portion of the subject, forexample, a portion of the heart. In some embodiments, method of imagingare provided. In some embodiments, methods and compositions forassessing perfusion and innervation mismatch in a portion of a subjectare provided.

In some embodiments, a compound is provided having formula:

R⁰—Ar-L-R¹

wherein

Ar is substituted or unsubstituted, monocyclic or bicyclic aryl; orsubstituted or unsubstituted, monocyclic or bicyclic heteroaryl;

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety; and

R⁰ is halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A2))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂,—NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1),—NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1),—C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1),—OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; and

R⁰ or R¹ is substituted with an imaging moiety selected from the groupconsisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I, or is associated with animaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator, or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or a saltthereof.

In some embodiments, a compound is provided having formula:

wherein

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is selected from the group consisting of:

wherein each occurrence of R^(B) is independently hydrogen, substitutedor unsubstituted alkyl, or a nitrogen-protecting group, provided atleast two R^(B) are hydrogen;

R² and R⁶ are hydrogen;

each of R³, R⁴ and R⁵ is independently hydrogen, halogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —OR^(A1), —N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1),—C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂, —OC(═O)R^(A1),—OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2),—NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂,—SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂,—C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1),—C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1),—OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂; orany two adjacent R³, R⁴ and R⁵ are joined to form an optionallysubstituted or unsubstituted carbocyclic, heterocyclic, aryl, orheteroaryl ring;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; and

wherein R⁴ is substituted with an imaging moiety selected from the groupconsisting of ¹⁸F, ⁷⁶Br, and ¹²⁴I; or is associated with an imagingmoiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr, ^(99m)Tc, and¹¹¹In through a chelator; or is ¹²⁴I;

or a salt thereof

with the proviso that if one of R³ or R⁵ is Cl, Br, or CF₃, then theother of R³ or R⁵ is not H.

In some embodiments, a compound is provided having formula:

wherein

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

R² is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

R³ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

each occurrence of R⁴ is independently hydrogen, halogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —OR^(A1), —N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1),—C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂, —OC(═O)R^(A1),—OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2),—NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂,—SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂,—C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1),—C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1),—OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring;

at least one R⁴ is substituted with an imaging moiety selected from thegroup consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is associated with animaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator; or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or a saltthereof.

In some embodiments, a compound is provided having formula:

wherein

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

R² is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

R³ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

R⁴ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

R⁴ is substituted with an imaging moiety selected from the groupconsisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is associated with animaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator; or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; or a salt thereof.

In some embodiments, a compound is provided having formula:

wherein

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

R² is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

R³ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

R⁴ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

R⁴ is substituted with an imaging moiety selected from the groupconsisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is associated with animaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator; or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; each occurrenceof R^(A1) is independently hydrogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl; andeach occurrence of R^(A2) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, or an amino protecting group, or two R^(A2)groups are joined to form an optionally substituted heterocyclic ring;or a salt thereof.

In some embodiments, a compound is provided having formula:

wherein

R⁹ and R¹⁰ are independently selected from the group consisting of H,—OR¹¹, F, Cl, Br, I, —CF₃, alkyl(C₁-C₄), and imaging moiety (I_(m));

R¹¹, R¹² and R¹³ are selected from the group consisting of H, alkyl, andaryl; and

W and X are independently selected from the group consisting of H, —OR₄,—N(R¹¹)₂, F, Cl, Br, —CF₃, I_(m), aryl, and heteroaryl;

wherein A) Y and Z are independently selected from the group consistingof —CH—, —CH₂—, —O—, —N—, —NR¹—, and —CH═CH— when a linking group Qbetween Y and Z is present or absent, wherein Q is selected from thegroup consisting of —CH—, —CH₂—, —CR¹¹—, —N—, —NH—, —NR—, —O—, and —S—;or

B) Y and Z are independently selected from the group consisting of H,—OR₄, —N(R¹¹)₂, F, Cl, Br, —CF₃, I_(m), aryl, and heteroaryl whenlinking group Q is absent;

wherein I_(m) is selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,and ¹³¹I, and is present in either W—Z or R⁹-R¹³, or a salt thereof.

In some embodiments, a compound is provided having formula:

wherein R⁹ is independently selected from the group consisting of H,—CF₃, and alkyl(C₁-C₄);

W, Y and Z are independently selected from the group consisting of H,—OR¹¹, —N(R¹¹)₂, F, Cl, Br, —CF₃, I_(m), aryl and heteroaryl; and

R¹¹ is selected from the group consisting of H, alkyl, and aryl;

wherein I_(m) is selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,and ¹³¹I, and is present in either W, Y, Z, R⁹, or R¹¹; or a saltthereof.

In some embodiments, a compound is provided having formula:

wherein W and Y are independently selected from the group consisting ofH, —OR¹¹, F, Cl, Br, —CF₃, and I_(m); and

R¹¹ is alkyl,

wherein I_(m) is selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,and ¹³¹I, and is present in either W, Y, or R¹¹; or a salt thereof.

In some embodiments, a compound is provided having formula:

In one aspect, the present invention provides pharmaceuticalcompositions comprising an inventive compound. The pharmaceuticalcomposition typically includes an amount of the inventive compoundsufficient to image a subject or a portion of the subject.Pharmaceutical compositions of the present invention may optionallyinclude a pharmaceutically acceptable excipient. Any mode ofadministration including oral and parenteral administration of aninventive compound or pharmaceutical composition thereof may be used.

In another aspect, the present invention provides methods of imaging asubject comprising administering an inventive compound to a subject; andacquiring an image of the subject or a portion of the subject. Compoundsof the invention or pharmaceutical compositions thereof may be used toimage an area of interest in a subject, including, but not limited to,the heart, a portion of the heart, the cardiovascular system, cardiacvessels, brain, and other organs. In certain embodiments, methods of theinvention include a method of imaging cardiac innervation and a methodof detecting norepinephrine transporter. In certain embodiments, thearea of the subject being imaged is imaged by positron emissiontomography (PET). A kit comprising an inventive compound or compositionand instructions for use is also provided by the present invention.

In another aspect, the present invention provides methods forsynthesizing an imaging agent by reacting an imaging agent precursorwith an imaging moiety or source thereof to form an imaging agent. Forexample, in certain embodiments, fluorination of an imaging agentprecursor comprising a leaving group (e.g., sulfonate leaving group) isperformed with a fully deprotected form of the precursor eliminating theneed for a subsequent deprotection step.

In another aspect, the present invention provides methods of selectingan antiarrhythmic agent and/or determining the dose of an antiarrhythmicagent for administration to a subject, the method comprising:

administering to the subject a compound as described herein or a saltthereof, or a compound of the formula:

R⁰—Ar-L-R¹

wherein

Ar is substituted or unsubstituted, monocyclic or bicyclic aryl; orsubstituted or unsubstituted, monocyclic or bicyclic heteroaryl;

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety; and

R⁰ is halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A2))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂,—NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1),—NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1),—C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1),—OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; and

R⁰ or R¹ is substituted with an imaging moiety selected from the groupconsisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I, or is associated with animaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator, or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or a saltthereof;

acquiring at least one image of a portion of the subject;

selecting the antiarrhythmic agent and/or determining the dose of anantiarrhythmic agent for administration to a subject based on the image.In some embodiments, wherein the imaging agent is:

or a pharmaceutically acceptable salt thereof. In some embodiments, theantiarrhythmic agent is an agent which is known to induceelectrophysiological changes in a subject's heart. In some embodiments,the antiarrhythmic agent is an agent which does not induceelectrophysiological changes in a subject's heart. In some embodiments,the electrophysiological changes comprise QT prolongation. In someembodiments, an antiarrhythmic agent that does not induceelectrophysiological changes in a subject's heart is selected based onthe image indicating the presence of cardiac denervation. In someembodiments, a reduced dose of an antiarrhythmic agent that induceselectrophysiological changes in a subject's heart is prescribed based onthe image indicating the presence of cardiac denervation.

In another aspect, the present invention provides methods comprisingadministering to the subject a compound described herein or a saltthereof, or a compound of the formula:

R⁰—Ar-L-R¹

wherein

Ar is substituted or unsubstituted, monocyclic or bicyclic aryl orsubstituted or unsubstituted, monocyclic or bicyclic heteroaryl;

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety; and

R⁰ is halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A2))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂,—NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1),—NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1),—C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1),—OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; and

R⁰ or R¹ is substituted with an imaging moiety selected from the groupconsisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I, or is associated with animaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator, or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or a saltthereof;

acquiring at least one image of a portion of the subject; and

identifying:

(i) a subject to be treated with an antiarrhythmic agent that does notinduce electrophysiological changes in the heart of the subject based onpresence of cardiac denervation in the image,

(ii) a subject to be treated with a reduced dose of an antiarrhythmicagent that induces electrophysiological changes in the heart of thesubject based on presence of cardiac denervation in the image, and/or

(iii) a subject in need of a dose reduction of an antiarrhythmic agentthat induces electrophysiological changes in the heart of the subjectbased on presence of cardiac denervation in the image. In someembodiments, the antiarrhythmic agent that induces electrophysiologicalchanges in the heart of the subject is a sodium channel blocker, apotassium channel blocker, or a calcium channel blocker. In someembodiments, the antiarrhythmic agent that induces electrophysiologicalchanges in the heart of the subject is a calcium channel blocker. Insome embodiments, the antiarrhythmic agent that induceselectrophysiological changes in the heart of the subject is quinidine,procainamide, disopyramide, lidocaine, phenytoin, mexiletine, tocainade,amiodarone, sotalol, ibutilide, dofetilide, dronedarone, E-4031,verapamil, or ditiazem. In some embodiments, the antiarrhythmic agentthat does not induce electrophysiological changes in the heart of thesubject is a beta-blocker. In some embodiments, the antiarrhythmic agentthat does not induce electrophysiological changes in the heart of thesubject is propranolol, esmolol, timolol, metoprolol, atenolol, orbisoprolol.

In some embodiments, a compound (e.g., an imaging agent precursor) isprovided having formula:

R⁰—Ar-L-R¹

wherein

Ar is substituted or unsubstituted, monocyclic or bicyclic aryl; orsubstituted or unsubstituted, monocyclic or bicyclic heteroaryl;

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R⁰ is halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A2))₂,—N(R^(A2))₃ ⁺, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —OSO₂R^(A1), —Si(R^(A1))₃,—Sn(R^(A1))₃, —B(OR^(A1))₂, —NR^(A2)SO₂R^(A1), —NO₂, —SO₂N(R^(A2))₂,—CN, —SCN, or —NO₂₂; and R⁰ is substituted with a leaving group or is aleaving group; and

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; or a salt thereof.

In some embodiments, a method is provided comprising reacting a compoundof formula:

R⁰—Ar-L-R¹

wherein

Ar is substituted or unsubstituted, monocyclic or bicyclic aryl; orsubstituted or unsubstituted, monocyclic or bicyclic heteroaryl;

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R⁰ is halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A2))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂,—NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1),—NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1),—C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1),—OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂; andR⁰ is substituted with a leaving group or is a leaving group;

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring;

or a salt, free base, or combination thereof;

with a fluorinating reagent under suitable conditions to form a compoundof formula:

R⁰—Ar-L-R¹

wherein R⁰ is substituted with a fluorine.

In some embodiments, a method of determining perfusion and innervationmismatch in a portion of a human subject is provided comprising:

administering to the subject a first imaging agent and acquiring atleast one first image of a portion of the subject, wherein the firstimaging agent is employed to image perfusion;

administering to the subject a second imaging agent and acquiring atleast one second image of the portion of the subject, wherein the secondimaging agent is employed to image innervation; and

determining regional mismatch of innervation and perfusion areas in theportion of the subject based at least in part on the at least one firstimage and the at least one second image, wherein the first imaging agenthas the structure:

wherein

J is selected from the group consisting of N(R²⁸), S, O, C(═O), C(═O)O,NHCH₂CH₂O, a bond, and C(═O)N(R²⁷);

when present, K is selected from the group consisting of hydrogen,alkoxyalkyl optionally substituted with an imaging moiety, alkyloxyoptionally substituted with an imaging moiety, aryl optionallysubstituted with an imaging moiety, C₁-C₆ alkyl optionally substitutedwith an imaging moiety, heteroaryl optionally substituted with animaging moiety, and an imaging moiety;

when present, L is selected from the group consisting of hydrogen,alkoxyalkyl optionally substituted with an imaging moiety, alkyloxyoptionally substituted with an imaging moiety, aryl optionallysubstituted with an imaging moiety, C₁-C₆ alkyl optionally substitutedwith an imaging moiety, heteroaryl optionally substituted with animaging moiety, and an imaging moiety;

M is selected from the group consisting of hydrogen, alkoxyalkyloptionally substituted with an imaging moiety, alkyloxy optionallysubstituted with an imaging moiety, aryl optionally substituted with animaging moiety, C₁-C₆ alkyl optionally substituted with an imagingmoiety, heteroaryl optionally substituted with an imaging moiety, and animaging moiety; or

L and M, together with the atom to which they are attached, may form athree- or four-membered carbocyclic ring;

Q is halo or haloalkyl;

n is 0, 1, 2, or 3;

R²¹, R²², R²⁷, and R²⁸ are independently selected from hydrogen, C₁-C₆alkyl optionally substituted with an imaging moiety, and an imagingmoiety;

R²³, R²⁴, R²⁵, and R²⁶ are independently selected from hydrogen,halogen, hydroxyl, alkyloxy, C₁-C₆ alkyl optionally substituted with animaging moiety, and an imaging moiety; R²⁹ is C₁-C₆ alkyl optionallysubstituted with an imaging moiety; and Y

is selected from the group consisting of a bond, carbon, and oxygen;provided that when Y is a bond, K and L are absent, and M is selectedfrom the group consisting of aryl optionally substituted with an imagingmoiety and heteroaryl optionally substituted with an imaging moiety; andprovided that when Y is oxygen, K and L are absent, and M is selectedfrom hydrogen, alkoxyalkyl optionally substituted with an imagingmoiety, aryl optionally substituted with an imaging moiety, C₁-C₆ alkyloptionally substituted with an imaging moiety, and heteroaryl optionallysubstituted with an imaging moiety; or a salt thereof, provided that atleast one imaging moiety is present.

In some embodiments, a method of assessing perfusion and innervationmismatch in a portion of a human subject is provided comprising:

administering to a subject a first imaging agent and acquiring at leastone first image of a portion of a subject, wherein the first imagingagent employed to image perfusion;

administering to a subject a second imaging agent and acquiring at leastone second image of the portion of the subject, wherein the secondimaging agent is employed to image innervation; and

determining regional mismatch of innervation and perfusion areas in theportion of the subject based at least in part on the at least one firstimage and the at least one second image, wherein the second imagingagent has the structure:

R⁰—Ar-L-R¹

wherein

Ar is substituted or unsubstituted, monocyclic or bicyclic aryl orsubstituted or unsubstituted, monocyclic or bicyclic heteroaryl;

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety; and

R⁰ is halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A2))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂,—NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1),—NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1),—C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1),—OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; and

R⁰ or R¹ is substituted with an imaging moiety selected from the groupconsisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I, or is associated with animaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator, or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or a saltthereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts non-limiting examples of imaging agents.

FIGS. 2 through 8 show images derived using non-limiting examples ofimaging agents.

FIG. 9 shows a plot of percent cell uptakes for non-limiting examples ofimaging agents.

FIG. 10 shows dose-response curves of a non-limiting imaging agent innon-limiting cell lines.

FIGS. 11 and 12 shows representative cardiac images and polar maps of anon-limiting imaging agent and a myocardial perfusion imaging agent.

FIG. 13A-FIG. 13C show representative time-activity curves derived froma non-limiting imaging agent and a myocardial perfusion imaging agent.

FIG. 14 shows image quantification to assess non-defect left ventricularareas in rabbits at varying time points according to some embodiments.

FIG. 15A shows examples of ECG tracings in rabbits before and duringdofetilide infusion.

FIG. 15B and FIG. 15C show changes in heart rate (HR) and QT_(cf)interval in rabbits, according to some embodiments.

FIG. 16A-FIG. 16C show images obtained using either Imaging Agent-1 orImaging Agent-2, for a control rabbit, a rabbit having globaldenervation, and a rabbit having regional denervation.

FIG. 17 shows images obtained using either Imaging Agent-1 or ImagingAgent-2, and corresponding polar maps for a control rabbit.

FIG. 18A-FIG. 18C show images obtained using either Imaging Agent-1 orImaging Agent-2, and corresponding polar maps for a rabbit havingregional denervation at 4 weeks, 13 weeks, and 46 weeks post-surgery.

FIG. 18D shows a plot of the % LV defect versus time for the imagesshown in FIG. 18A-FIG. 18C.

Other aspects, embodiments, and features of the invention will becomeapparent from the following detailed description when considered inconjunction with the accompanying drawings. The accompanying figures areschematic and are not intended to be drawn to scale. For purposes ofclarity, not every component is labeled in every figure, nor is everycomponent of each embodiment of the invention shown where illustrationis not necessary to allow those of ordinary skill in the art tounderstand the invention. All patent applications and patentsincorporated herein by reference are incorporated by reference in theirentirety. In case of conflict, the present specification, includingdefinitions, controls.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds, compositions thereof, systemscomprising such compounds, reagents, cassettes, methods, kits, andapparatuses for the synthesis and/or use of imaging agents andprecursors thereof. In some aspects, the invention generally relates toan imaging agent of Formula (Ia)-(Id), (IIa)-(IIb), (III), (IV),(Va)-(Vd), (VI), or (VII). The imaging agents of the invention may beused to image an area of interest in a subject, including, but notlimited to, the heart, a portion of the heart, the cardiovascularsystem, cardiac vessels, brain, and other organs. In certainembodiments, the area of the subject being imaged is imaged by positronemission tomography (PET). The present invention also provides methodsfor synthesizing an imaging agent by reacting an imaging agent precursorwith an imaging moiety or source thereof to form an imaging agent.

In some embodiments, methods and compositions for assessing perfusionand innervation mismatch in a portion in a subject, for example, a humansubject, are provided. In some embodiments, the methods and compositionsmay be employed for assessing perfusion and innervation mismatch in asubject following a tissue insult. In some embodiments, the tissueinsult is a cardiac insult, for example, a myocardial infarction. Insome embodiments, the portion of the subject is the heart or a portionof the heart.

A. Imaging Agents

In one aspect, the invention provides compounds useful as imaging agentsfor imaging a subject or an area of interest of a subject. In certainembodiments, the imaging agent is labeled with ¹⁸F and is useful in PETimaging.

In some embodiments, a compound is provided comprising Formula (Ia):

R⁰—Ar-L-R¹  (Ia)

wherein

Ar is substituted or unsubstituted, monocyclic or bicyclic aryl; orsubstituted or unsubstituted, monocyclic or bicyclic heteroaryl;

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety; and

R⁰ is halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A2))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂,—NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1),—NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1),—C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1),—OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; and

R⁰ or R¹ is substituted with an imaging moiety selected from the groupconsisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I, or is associated with animaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator, or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or a saltthereof.

In certain embodiments, the compound of Formula (Ia) is not of theformula:

In some embodiments, a compound is provided comprising Formula (Ib):

R⁰—Ar-L-R¹  (Ib)

wherein

Ar is substituted or unsubstituted, monocyclic or bicyclic aryl; orsubstituted or unsubstituted, monocyclic or bicyclic heteroaryl;

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

R⁰ is halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A2))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂,—NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1),—NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1),—C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1),—OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; and

R⁰ or R¹ is substituted with an imaging moiety selected from the groupconsisting of ¹⁸F, ⁷⁶Br, and ¹²⁴I, or is associated with an imagingmoiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr, ^(99m)Tc, and¹¹¹In through a chelator, or is an imaging moiety selected from thegroup consisting of ¹⁸F, ⁷⁶Br, and ¹²⁴I; or a salt thereof;

provided that when Ar is phenyl, when L is —CH₂—, when R¹ is

and when R⁰ is an imaging moiety selected from the group consisting of¹⁸F, ⁷⁶Br, and ¹²⁴I, then Ar is substituted with substituents other than—R⁰ and -L-R¹.

In some embodiments, a compound of Formula (Ib) is not of the formula:

In some embodiments, a compound is provided comprising Formula (Ic):

R⁰—Ar-L-R¹  (Ic)

wherein

Ar is substituted or unsubstituted, monocyclic or bicyclic aryl; orsubstituted or unsubstituted, monocyclic or bicyclic heteroaryl;

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

R⁰ is halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A2))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂,—NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1),—NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1),—C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1),—OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; and

R⁰ or R¹ is substituted with an imaging moiety selected from the groupconsisting of ¹⁸F, ⁷⁶Br, and ¹²⁴I, or is associated with an imagingmoiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr, ^(99m)Tc, and¹¹¹In through a chelator, or is an imaging moiety selected from thegroup consisting of ¹⁸F, ⁷⁶Br, and ¹²⁴I; or a salt thereof;

provided that when Ar is phenyl, then R⁰ is not ¹⁸F; and

further provided that when Ar is phenyl, when L is —CH₂—, when R¹ is

and when R⁰ is an imaging moiety selected from the group consisting of⁷⁶Br and ¹²⁴I, then Ar is substituted with substituents other than —R⁰and -L-R¹.

In some embodiments, a compound of Formula (Ic) is not of the formula:

In some embodiments, a compound is provided comprising Formula (Id):

R⁰—Ar-L-R¹  (Id)

wherein

Ar is substituted or unsubstituted, monocyclic or bicyclic aryl; orsubstituted or unsubstituted, monocyclic or bicyclic heteroaryl;

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

R⁰ is halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A2))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂,—NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1),—NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1),—C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1),—OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; and

R⁰ or R¹ is substituted with an imaging moiety selected from the groupconsisting of ¹⁸F, ⁷⁶Br, and ¹²⁴I, or is associated with an imagingmoiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr, ^(99m)Tc, and¹¹¹In through a chelator, or is an imaging moiety selected from thegroup consisting of ¹⁸F, ⁷⁶Br, and ¹²⁴I; or a salt thereof;

provided that when Ar is phenyl, then R⁰ is not ¹⁸F;

further provided that when Ar is phenyl, when L is —CH₂—, when R¹ is

and when R⁰ is an imaging moiety selected from the group consisting of⁷⁶Br and ¹²⁴I, then Ar is substituted with substituents other than —R⁰and -L-R¹; and

further provided that when Ar is phenyl, then Ar is not substituted with—OH.

In some embodiments, a compound of Formula (Id) is not of the formula:

In certain embodiments, a compound of Formula (Ia), (Ib), (Ic), or (Id)is any suitable salt, as described herein. In certain embodiments, acompound of Formula (Ia), (Ib), (Ic), or (Id) is a pharmaceuticallyacceptable salt. Non-limiting examples of salts include mesylate (i.e.,methanesulfonate), phosphate, sulfate, acetate, formate, benzoate,chloride, iodide, bromide, ascorbate, trifluoroacetate, or tosylate saltof a compound of Formula (Ia), (Ib), (Ic), or (Id).

As described above, in some embodiments for a compound of Formula (Ia),R⁰ or R¹ is substituted with an imaging moiety selected from the groupconsisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I, or is associated with animaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator, or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I. In certainembodiments, the imaging moiety is ¹⁸F. In certain embodiments, theimaging moiety is ⁷⁶Br. In certain embodiments, the imaging moiety is¹²⁴I. In certain embodiments, the imaging moiety is ¹³¹I. In some cases,the imaging moiety is not ¹³¹I. In some cases, the imaging moiety is¹⁸F, ⁷⁶Br, or ¹²⁴I. In some cases, the imaging moiety is ¹⁸F or ⁷⁶Br. Insome embodiments, the imaging moiety is not directly bound to Ar. Incertain embodiments, R⁰ is substituted with an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is associatedwith an imaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator; or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I. In certainembodiments, R⁰ is substituted with an imaging moiety selected from thegroup consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I. In certain embodiments,R⁰ is associated with an imaging moiety selected from the groupconsisting of ⁶⁴Cu, ⁸⁹Zr, ^(99m)Tc, and ¹¹¹In through a chelator. Incertain embodiments, R⁰ is an imaging moiety selected from the groupconsisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I. In some embodiments, R¹ is:substituted with an imaging moiety selected from the group consisting of¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is associated with an imaging moietyselected from the group consisting of ⁶⁴Cu, ⁸⁹Zr, ^(99m)Tc, and ¹¹¹Inthrough a chelator; or is an imaging moiety selected from the groupconsisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I. In some cases, R¹ issubstituted with an imaging moiety selected from the group consisting of¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I. In some cases, R¹ is substituted with ¹⁸F.

As described above, in some embodiments for a compound of Formula (Ib),(Ic), or (Id), R⁰ or R¹ is substituted with an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, and ¹²⁴I, or is associated withan imaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator, or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, and ¹²⁴I. In certainembodiments, the imaging moiety is ¹⁸F. In certain embodiments, theimaging moiety is ⁷⁶Br. In certain embodiments, the imaging moiety is¹²⁴I. In certain embodiments, the imaging moiety is ¹³¹I. In certainembodiments, the imaging moiety is not ¹³¹I. In some cases, the imagingmoiety is not ¹³¹I. In some cases, the imaging moiety is ¹⁸F, ⁷⁶Br, or¹²⁴I. In some cases, the imaging moiety is ¹⁸F or ⁷⁶Br. In someembodiments, the imaging moiety is not directly bound to Ar. In certainembodiments, R⁰ is substituted with an imaging moiety selected from thegroup consisting of ¹⁸F, ⁷⁶Br, and ¹²⁴I; or is associated with animaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator; or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, and ¹²⁴I. In certainembodiments, R⁰ is substituted with an imaging moiety selected from thegroup consisting of ¹⁸F, ⁷⁶Br, and ¹²⁴I. In certain embodiments, R⁰ isassociated with an imaging moiety selected from the group consisting of⁶⁴Cu, ⁸⁹Zr, ^(99m)Tc, and ¹¹¹In through a chelator. In certainembodiments, R⁰ is an imaging moiety selected from the group consistingof ¹⁸F, ⁷⁶Br, and ¹²⁴I. In certain embodiments, the imaging moiety is¹⁸F. In some embodiments, R¹ is substituted with an imaging moietyselected from the group consisting of ¹⁸F, ⁷⁶Br, and ¹²⁴I; or isassociated with an imaging moiety selected from the group consisting of⁶⁴Cu, ⁸⁹Zr, ^(99m)Tc, and ¹¹¹In through a chelator; or is an imagingmoiety selected from the group consisting of ¹⁸F, ⁷⁶Br, and ¹²⁴I. Insome cases, R¹ is substituted with an imaging moiety selected from thegroup consisting of ¹⁸F, ⁷⁶Br, and ¹²⁴I. In some cases, R¹ issubstituted with ¹⁸F.

As described above, in some embodiments for a compound of Formula (Ia),(Ib), (Ic), or (Id), Ar may be substituted or unsubstituted, monocyclicor bicyclic aryl; or substituted or unsubstituted, monocyclic orbicyclic heteroaryl. As described above, in some embodiments, theimaging moiety is not directly bound to Ar. In certain embodiments, when¹⁸F is the imaging moiety, then ¹⁸F is not bound directly to Ar. Incertain embodiments, when ¹⁸F is the imaging moiety and Ar is phenylthen ¹⁸F is not bound directly to Ar. In other embodiments, when ⁷⁶Br isthe imaging moiety, then ⁷⁶Br is not bound directly to Ar. In otherembodiments, when ⁷⁶Br is the imaging moiety and Ar is phenyl then ⁷⁶Bris not bound directly to Ar. In other embodiments, when ¹²⁴I is theimaging moiety then ¹²⁴I is not bound directly to Ar. In otherembodiments, when ¹²⁴I is the imaging moiety and Ar is phenyl then ¹²⁴Iis not bound directly to Ar. In other embodiments, when ¹³¹I is theimaging moiety, then ¹³¹I is not bound directly to Ar. In otherembodiments, when ¹³¹I is the imaging moiety and Ar is phenyl then ¹³¹Iis not bound directly to Ar. However, in other embodiments, the imagingmoiety is directly bound to Ar. In some embodiments, when Ar is phenylthen the imaging moiety is not present in R⁰. In some embodiments, whenAr is phenyl then the imaging moiety is not present in R⁰ when R⁰ isOR^(A1) and R^(A1) is alkyl. In some embodiments, when Ar is phenyl thenthe imaging moiety is not present in R⁰, when R⁰ is alkyl.

In certain embodiments, for a compound of Formula (Ia), (Ib), (Ic), or(Id), Ar is selected from the group consisting of substituted orunsubstituted phenyl, substituted or unsubstituted naphthyl, substitutedor unsubstituted biphenyl, substituted or unsubstituted heteroaryl,substituted or unsubstituted monocyclic heteroaryl, substituted orunsubstituted bicyclic heteroaryl, substituted or unsubstitutedbenzoxazolyl, substituted or unsubstituted benzimidazoly, substituted orunsubstituted benzthiazolyl, substituted or unsubstituted indolyl,substituted or unsubstituted quinolinyl, substituted or unsubstitutedisoquinolinyl, substituted or unsubstituted chromanyl, substituted orunsubstituted chromenyl, substituted or unsubstituted benzofuranyl, orsubstituted or unsubstituted benzpyrazolyl. In certain embodiments, Aris substituted or unsubstituted aryl. In some embodiments, Ar issubstituted or unsubstituted phenyl. In other embodiments, Ar is notphenyl. In some embodiments, Ar is substituted or unsubstitutednaphthyl. In some embodiments, Ar is substituted or unsubstitutedbiphenyl. In some embodiments, Ar is substituted or unsubstitutedheteroaryl. In some embodiments, Ar is substituted or unsubstitutedmonocyclic heteroaryl. In some embodiments, Ar is substituted orunsubstituted bicyclic heteroaryl. In certain embodiments, Ar issubstituted or unsubstituted, 10-membered heteroaryl. In certain,embodiments, Ar is substituted or unsubstituted, 9-membered heteroaryl.In certain embodiments, Ar is substituted or unsubstituted 8-memberedheteroaryl. In some embodiments, Ar is substituted or unsubstitutedbenzoxazolyl. In some embodiments, Ar is substituted or unsubstitutedbenzimidazolyl. In some embodiments, Ar is substituted or unsubstitutedbenzthiazolyl. In some embodiments, Ar is substituted or unsubstitutedindolyl. In some embodiments, Ar is substituted or unsubstitutedquinolinyl. In some embodiments, Ar is substituted or unsubstitutedisoquinolinyl. In some embodiments, Ar is substituted or unsubstitutedchromanyl. In some embodiments, Ar is substituted or unsubstitutedchromenyl. In some embodiments, Ar is substituted or unsubstitutedbenzofuranyl. In some embodiments, Ar is substituted or unsubstitutedbenzpyrazolyl. In some embodiments, Ar is substituted or unsubstitutedindazolyl. In some embodiments, Ar is substituted or unsubstitutedbenztriazolyl.

As described above, in some embodiments for a compound of Formula (Ia),(Ib), (Ic), or (Id), L may be a bond; substituted or unsubstituted,cyclic or acyclic alkylene; substituted or unsubstituted, cyclic oracyclic alkenylene; substituted or unsubstituted, cyclic or acyclicalkynylene; or substituted or unsubstituted, cyclic or acyclicheteroaliphatic. L may be of any suitable length. In some cases, Lranges from 0 to 6 atoms in length, from 0 to 3 atoms in length, or from0 to 2 atoms in length. In certain embodiments, L is 0, 1, 2, 3, 4, 5,or 6 atoms in length. The length of L may be determined by determiningthe number of atoms in the shortest distance from Ar to R¹, wherein R¹begins at the first atom of R¹ or N. In some cases, when determining thelength of L, the substituents are not considered.

In some embodiments, L is selected from the group consisting of a bond;substituted or unsubstituted, cyclic or acyclic C₁₋₆alkylene;unsubstituted, acyclic C₁₋₆alkylene; acyclic C₁₋₆alkylene; substitutedor unsubstituted, cyclic or acyclic C₁₋₆alkenylene; or substituted orunsubstituted, and cyclic or acyclic heteroaliphatic.

In some embodiments, L is selected from the group consisting of —CR′₂—,—CR′₂CR′₂—, —CR′₂CR′₂CR′₂—, —CR′═CR′—, —CR′═CR′CR′₂—, —CR′₂CR′═CR′—,—OCR′₂—, —CR′₂O—, —OCR′₂CR′₂—, —CR′₂CR′₂O—, —NR′CR′₂—, —CR′₂NR′—,—NR′CR′₂C R′₂—, —CR′₂C, R′₂NR′—, —CR′═N—, —N═CR′—,

wherein R′ is independently hydrogen, halogen, —OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted alkoxy, or substituted or unsubstituted alkoxyalkyl.

In some embodiments, L is a bond. In some embodiments, L is selectedfrom the group consisting of —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH═CH—,—CH═CHCH₂—, —CH₂CH═CH—, —OCH₂—, —CH₂O—, —OCH₂CH₂—, —CH₂CH₂O—, —NHCH₂—,—CH₂NH—, —NHCH₂CH₂—, —CH₂CH₂NH—, —CH═N—, —N═CH—,

each optionally substituted.

In some embodiments, L is substituted or unsubstituted, cyclic oracyclic alkylene. In some embodiments, L is substituted orunsubstituted, cyclic or acyclic C₁₋₆alkylene. In some embodiments, L isunsubstituted, acyclic C₁₋₆alkylene. In some embodiments, L issubstituted, acyclic C₁₋₆alkylene. In some embodiments, L is —CH₂—. Insome embodiments, L is —CH₂CH₂—. In some embodiments, L is —CH₂CH₂CH₂—.In some embodiments, L is —CH═CH—. In some embodiments, L is substitutedor unsubstituted, cyclic or acyclic C₁₋₆alkenylene. In some embodiments,L is substituted or unsubstituted, cyclic or acyclic heteroaliphatic. Insome embodiments, L is —OCH₂— or —CH₂O—. In some embodiments, L is—OCH₂CH₂— or —CH₂CH₂O—. In some embodiments, L is —NHCH₂— or —CH₂NH—. Insome embodiments, L is —NHCH₂CH₂— or —CH₂CH₂NH—. In some embodiments, Lis —CH═N— or —N═CH—. In some embodiments, L is —CH₂CH₂CH₂—. In someembodiments, L is:

In some embodiments, L is:

In some embodiments, L is:

In some embodiments, L is:

In some embodiments, L is:

In some embodiments, L is:

In some embodiments, L is:

In some embodiments, L is:

In some embodiments, L is:

In some embodiments, L is:

Each of the L groups described herein may be combined with any suitableAr, R¹, and/or R⁰ group, or combinations described herein.

As described above, in some embodiments for a compound of Formula (Ia),(Ib), (Ic), or (Id), R¹ is a substituted or unsubstitutednitrogen-containing moiety. In some embodiments, R¹ is —N(R^(A))₂,heteroaryl, heterocyclic, —C(═NH)NH₂, —NHC(═NH)NH₂,—NR^(A)C(═NR^(A))N(R^(A))₂, —NHC(═NH)NHR^(A), or —NHC(═NH)N(R^(A))₂,wherein each occurrence of R^(A) is independently hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl, or twoR^(A) groups may be joined to form an optionally substitutedheterocyclic ring. In some embodiments, R¹ is a non-aromatic, cyclic,substituted or unsubstituted nitrogen-containing moiety. In someembodiments, R¹ is selected from the group consisting of —NHC(═NH)NH₂,—NH₂, —NHR^(A) (wherein R^(A) is as defined herein), —NHCH₃, —NHCH₂CH₃,—NHCH₂CH₂CH₃,

each optionally substituted, wherein each occurrence of R^(B) isindependently hydrogen, substituted or unsubstituted alkyl, or anitrogen-protecting group. In some cases, at least two R^(B) arehydrogen.

In some embodiments, R¹ is —NHC(═NH)NH₂. In some embodiments, R¹ is:

wherein each occurrence of R^(B) is independently hydrogen, substitutedor unsubstituted alkyl, or a nitrogen-protecting group, provided atleast two R^(B) are hydrogen. In some embodiments, R¹ is:

wherein R^(B) is hydrogen, substituted or unsubstituted alkyl, or anitrogen-protecting group.

However, in other embodiments, R¹ is not —NHC(═NH)NH₂. In someembodiments, R¹ is not:

wherein each occurrence of R^(B) is independently hydrogen, substitutedor unsubstituted alkyl, or a nitrogen-protecting group, provided atleast two R^(B) are hydrogen. In some embodiments, R¹ is not:

wherein R^(B) is hydrogen, substituted or unsubstituted alkyl, or anitrogen-protecting group. In certain embodiments, when L is —CH₂—, thenR¹ is not —NHC(═NH)NH₂. In certain embodiment, when L is —CH₂—, and Aris phenyl, then R¹ is not —NHC(═NH)NH₂.

In some embodiments, R¹ is —NH₂. In some embodiments, R¹ is —NHR^(A). Insome embodiments, R¹ is —NHCH₃, —NHCH₂CH₃, or —NHCH₂CH₂CH₃. In someembodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

wherein each occurrence of R^(B) is independently hydrogen, substitutedor unsubstituted alkyl, or a nitrogen-protecting group, provided atleast two R^(B) are hydrogen. In some embodiments, R¹ is:

wherein R^(B) is hydrogen, substituted or unsubstituted alkyl, or anitrogen-protecting group. In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

wherein each occurrence of R^(B) is independently hydrogen, substitutedor unsubstituted alkyl, or a nitrogen-protecting group, provided atleast two R^(B) are hydrogen. In some embodiments, R¹ is:

wherein R^(B) is hydrogen, substituted or unsubstituted alkyl, or anitrogen-protecting group. In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

wherein each occurrence of R^(B) is independently hydrogen, substitutedor unsubstituted alkyl, or a nitrogen-protecting group, provided atleast two R^(B) are hydrogen. In some embodiments, R¹ is:

wherein R^(B) is hydrogen, substituted or unsubstituted alkyl, or anitrogen-protecting. group. In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

wherein each occurrence of R^(B) is independently hydrogen, substitutedor unsubstituted alkyl, or a nitrogen-protecting group, provided atleast two R^(B) are hydrogen. In some embodiments, R¹ is:

wherein R^(B) is hydrogen, substituted or unsubstituted alkyl, or anitrogen-protecting group.In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

Each of the R¹ groups described herein may be combined with any suitableAr, R⁰, and/or L groups and combinations described herein, for example,as described in connection with a compound of Formula (Ia), (Ib), (Ic),or (Id). For example, in certain embodiments, when L is a bond; R¹ is:

As another example, in certain embodiments, when L is a bond; Ar isphenyl; and R¹ is:

then Ar is substituted with at least one other group besides R⁰ and-L-R¹. As another example, in certain embodiments, when L is a bond; Aris not phenyl; and R¹ is:

then Ar is substituted with at least one other group besides R⁰ and-L-R¹.

As yet another example, in certain embodiments, when L is —CH₂—; then R¹is —NHC(═NH)NH₂. In some embodiments, Ar is phenyl; L is —CH₂—; and R¹is —NHC(═NH)NH₂. In some embodiments, Ar is not phenyl; L is —CH₂—; andR¹ is —NHC(═NH)NH₂.

In some embodiments, for a compound of Formula (Ia), (Ib), (Ic), or(Id), when Ar is phenyl, Ar is not substituted with a hydroxyl group. Insome embodiments, when Ar is phenyl, Ar is not substituted with ahydroxyl group or a halogen. In some embodiments, when Ar is phenyl, andR⁰ is alkyl substituted with an imaging moiety, then Ar is notsubstituted with a hydroxyl group. In some embodiments, when Ar isphenyl, and R⁰ is alkoxy substituted with an imaging moiety, then Ar isnot substituted with a hydroxyl group. In some embodiments, when Ar isphenyl, and the imaging moiety is attached directly to the phenyl ring,then the phenyl ring is not substituted with a hydroxyl group orunsubstituted except with R⁰ and -L-R¹.

In some embodiments, when Ar is phenyl, L is —CH₂—, R¹ is:

and R⁰ is alkoxy substituted with an imaging moiety, then Ar is notsubstituted with a halogen. In some embodiments, when Ar is phenyl, R⁰is alkoxymethyl substituted with an imaging moiety, and R¹ is:

then L is —CH₂—. In some embodiments, when Ar is phenyl, L is —CH₂—, R¹is:

and R⁰ is alkoxy substituted with an imaging moiety or alkyl substitutedwith an imaging moiety, then Ar is not substituted with a halogen orunsubstituted except with R⁰ and -L-R¹. In some embodiments, when Ar isphenyl, R¹ is:

and R⁰ is alkoxy substituted with an imaging moiety, then L is not:

In some embodiments, when Ar is phenyl, and L is a bond, then R¹ is not:

In some embodiments, when Ar is phenyl, L is a bond, and R¹ is:

then R⁰ is not an imaging moiety directly attached to the phenyl ring,alkyl substituted with an imaging moiety, alkoxyalkyl substituted withan imaging moiety, or alkoxy substituted with an imaging moiety.

In some embodiments, one, two, three, four, or five of the followinga)-e) apply to a compound of Formula (Ia), (Ib), (Ic), or (Id), wheresuitable:

-   -   a) Ar is a substituted or unsubstituted group selected from the        group consisting of phenyl, naphthyl, biphenyl, monocyclic        heteroaryl, and bicyclic heteroaryl;    -   b) Ar is not phenyl;    -   c) L is selected from the group consisting of a bond;        substituted or unsubstituted, cyclic or acyclic C₁₋₆alkylene;        unsubstituted, acyclic C₁₋₆alkylene; acyclic C₁₋₆alkylene;        substituted or unsubstituted, cyclic or acyclic C₁₋₆alkenylene;        and substituted or unsubstituted, cyclic or acyclic        heteroaliphatic;    -   d) R¹ is selected from the group consisting of —N(R^(A))₂,        heteroaryl, heterocyclic, —C(═NH)NH₂, —NHC(═NH)NH₂,        —NR^(A)C(═NR^(A))N(R^(A))₂; —NHC(═NH)NHR^(A), and        —NHC(═NH)N(R^(A))₂, wherein R^(A) is as described herein;    -   e) R⁰ is substituted with an imaging moiety selected from the        group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is associated        with an imaging moiety selected from the group consisting of        ⁶⁴Cu, ⁸⁹Zr, ^(99m)Tc, and ¹¹¹In through a chelator; or is an        imaging moiety selected from the group consisting of ¹³F, ⁷⁶Br,        ¹²⁴I, and ¹³¹I.

In some embodiments, one, two, three, four, five, six, or seven of thefollowing a)-g) apply to a compound of Formula (Ia), (Ib), (Ic), or(Id), where suitable:

-   -   a) Ar is a substituted or unsubstituted group selected from the        group consisting of phenyl, naphthyl, biphenyl, benzothiazolyl,        indolyl, quinolinyl, isoquinolinyl, chromanyl, chromenyl,        benzofuranyl, and benzpyrazolyl;    -   b) Ar is not phenyl;    -   c) L is selected from the group consisting of a bond; —CH₂—,        —CH₂CH₂—, —CH₂CH₂CH₂—, —CH═CH—, —OCH₂—, —CH₂O—, —OCH₂CH₂—,        —CH₂CH₂O—, —NHCH₂—, —CH₂NH—, —NHCH₂CH₂—, —CH₂CH₂NH—, —CH═N—,        —N═CH—, —CH₂CH₂CH₂—,

-   -   d) R¹ is selected from the group consisting of —NHC(═NH)NH₂,        —NH₂, —NHR^(A), —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃,

each optionally substituted, wherein each occurrence of R^(B) isindependently hydrogen, substituted or unsubstituted alkyl, or anitrogen-protecting group, provided at least two R^(B) are hydrogen;

-   -   e)R¹ is not —NHC(═NH)NH₂;    -   f) R¹ is substituted with an imaging moiety selected from the        group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is an imaging        moiety selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,        and ¹³¹I;    -   g) R⁰ is substituted with an imaging moiety selected from the        group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is an imaging        moiety selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,        and ¹³¹I.

In certain embodiments, a compound of Formula (Ia) comprises Formula(IIa):

wherein

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

each of R²-R⁶ is independently hydrogen, halogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,—OR^(A1), —N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1),—C(═O)SR^(A1), —C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1),—OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2),—NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂,—SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂,—C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1),—C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1),—OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂; orany two adjacent R²-R⁶ are joined to form an optionally substituted orunsubstituted carbocyclic, heterocyclic, aryl, or heteroaryl ring;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; and

one or more of R¹-R⁶ is substituted with an imaging moiety selected fromthe group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is associated withan imaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator; or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or a saltthereof.

As described above for a compound of Formula (IIa), one or more of R¹-R⁶is substituted with an imaging moiety selected from the group consistingof ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is associated with an imaging moietyselected from the group consisting of ⁶⁴Cu, ⁸⁹Zr, ^(99m)Tc, and ¹¹¹Inthrough a chelator; or is an imaging moiety selected from the groupconsisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I. In some embodiments, one ofR¹-R⁶ is substituted with an imaging moiety selected from the groupconsisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is associated with animaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator; or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I. In certainembodiments, the imaging moiety is ¹⁸F. In certain embodiments, theimaging moiety is ⁷⁶Br. In certain embodiments, the imaging moiety is¹²⁴I. In certain embodiments, the imaging moiety is ¹³¹I. In some cases,the imaging moiety is not ¹³¹I. In some cases, the imaging moiety is¹⁸F, ⁷⁶Br, or ¹²⁴I. In some cases, the imaging moiety is ¹⁸F or ⁷⁶Br.

In some cases, R⁴ is substituted with an imaging moiety selected fromthe group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is associated withan imaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator; or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I. In someembodiments, R⁴ is substituted with an imaging moiety selected from thegroup consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I. In some embodiments, R⁴is substituted with an imaging moiety selected from the group consistingof ¹⁸F.

In some embodiments, R⁴ is selected from the group consisting ofhydrogen, halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A2))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂,—NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1),—NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1),—C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1),—OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂.

In some embodiments, for a compound of Formula (IIa), R⁴ is selectedfrom the group consisting of C₁₋₆alkyl, alkoxy, and alkoxyalkyl, eachoptionally substituted with an imaging moiety, or any combination of R⁴groups in this list. In some cases, R⁴ is alkoxymethyl, optionallysubstituted with the imaging moiety. In some cases, R⁴ is selected fromthe group consisting of —CH₂F, —CH₂CH₂F, —CH₂CH₂CH₂F, —CH₂CH₂CH₂CH₂F,—OCH₂F, —OCH₂CH₂F, —OCH₂CH₂CH₂F, —OCH₂CH₂CH₂CH₂F, —CH₂OCH₂F,—CH₂OCH₂CH₂F, —CH₂OCH₂CH₂CH₂F, and —CH₂OCH₂CH₂CH₂CH₂F. In some cases,the F is isotopically enriched with ¹⁸F.

In some embodiments, R⁴ is C₁₋₆alkyl. In some embodiments, R⁴ is alkylsubstituted with an imaging moiety. In some embodiments, R⁴ is —CH₂F,—CH₂CH₂F, —CH₂CH₂CH₂F, or —CH₂CH₂CH₂CH₂F. In some cases, the F isisotopically enriched with ¹⁸F. In some embodiments, R⁴ is alkoxysubstituted with an imaging moiety. In some embodiments, R⁴ is —OCH₂F,—OCH₂CH₂F, —OCH₂CH₂CH₂F, or —OCH₂CH₂CH₂CH₂F. In some cases, the F isisotopically enriched with ¹⁸F. In some embodiments, R⁴ is alkoxyalkylsubstituted with an imaging moiety. In some embodiments, R⁴ is of theformula:

wherein n is an integer between 0 and 6, inclusive; and m is an integerbetween 0 and 6, inclusive. In some embodiments, R⁴ is alkoxymethylsubstituted with an imaging moiety. In some embodiments, R⁴ is—CH₂OCH₂F, —CH₂OCH₂CH₂F, —CH₂OCH₂CH₂CH₂F, or —CH₂OCH₂CH₂CH₂CH₂F. In somecases, the F is isotopically enriched with ¹⁸F.

Additional examples of R⁴ groups which may be used in connection with acompound of Formula (IIa) are described herein, for example, inconnection with a compound of Formula (IV).

In some embodiments, R⁴ is selected from the group consisting ofhalogen; alkoxy, optionally substituted; C₁₋₆alkyl, optionallysubstituted; —CN; and —OH. In some embodiments, R³ is selected from thegroup consisting of fluorine, chlorine, bromine, iodine, —CF₃, OCH₃,—OH, —CH₃, and —CN.

In some embodiments, R⁴ is halogen. In some embodiments, R⁴ is fluorine.In some embodiments, R⁴ is isotopically enriched with ¹⁸F. In someembodiments, R⁴ is chlorine. In some embodiments, R⁴ is bromine. In someembodiments, R⁴ is iodine. In some embodiments, R⁴ is —CF₃. In someembodiments, R⁴ is alkoxy. In some embodiments, R⁴ is substitutedalkoxy. In some embodiments, R³ is —OCH₃. In some embodiments, R⁴ is—OH. In some embodiments, R⁴ is C₁₋₆alkyl. In some embodiments, R⁴ is—CH₃. In some embodiments, R⁴ is —CN. Additional examples of R⁴ groupswhich may be used in connection with a compound of Formula (IIa) aredescribed below in connection with a compound of Formula (IV).

Furthermore, each of the R⁴ groups described herein in connection with acompound of Formula (IIa) may be combined with any suitable R¹ and/or Lgroup as described herein, for example, in connection with a compound ofFormula (Ia)-(Id).

In some cases, for a compound of Formula (IIa), R³ is substituted withan imaging moiety selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,and ¹³¹I; or is associated with an imaging moiety selected from thegroup consisting of ⁶⁴Cu, ⁸⁹Zr, ^(99m)Tc, and ¹¹¹In through a chelator;or is an imaging moiety selected from the group consisting of ¹⁸F, ⁷⁶Br,¹²⁴I, and ¹³¹I. In some embodiments, R³ is substituted with an imagingmoiety selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I.In some embodiments, R³ is substituted with an imaging moiety selectedfrom the group consisting of ¹⁸F. In some embodiments, R³ is halogen. Insome embodiments, R³ is fluorine. In some embodiments, R³ isisotopically enriched with ¹⁸F.

In some embodiments, for a compound of Formula (IIa), R³ is selectedfrom the group consisting of hydrogen, halogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,—OR^(A1), —N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1),—C(═O)SR^(A1), —C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1),—OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2),—NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂,—SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂,—C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1),—C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1),—OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂.

In some embodiments, R³ is selected from the group consisting ofC₁₋₆alkyl, alkoxy, and alkoxyalkyl, each optionally substituted with animaging moiety, or any combination of R³ groups in this list. In somecases, R³ is alkoxymethyl, optionally substituted with the imagingmoiety. In some cases, R³ is selected from the group consisting of—CH₂F, —CH₂CH₂F, —CH₂CH₂CH₂F, —CH₂CH₂CH₂CH₂F, —OCH₂F, —OCH₂CH₂F,—OCH₂CH₂CH₂F, —OCH₂CH₂CH₂CH₂F, —CH₂OCH₂F, —CH₂OCH₂CH₂F, —CH₂OCH₂CH₂CH₂F,and —CH₂OCH₂CH₂CH₂CH₂F. In some cases, the F is isotopically enriched in¹⁸F.

In some embodiments, R³ is C₁₋₆alkyl. In some embodiments, R³ is alkylsubstituted with an imaging moiety. In some embodiments, R³ is —CH₂F,—CH₂CH₂F, —CH₂CH₂CH₂F, or —CH₂CH₂CH₂CH₂F. In some embodiments, R³ isalkoxy substituted with an imaging moiety. In some embodiments, R³ is—OCH₂F, —OCH₂CH₂F, —OCH₂CH₂CH₂F, or —OCH₂CH₂CH₂CH₂F. In someembodiments, R³ is alkoxyalkyl substituted with an imaging moiety. Insome embodiments, R³ is of the

wherein n is an integer between 0 and 6, inclusive; and m is an integerbetween 0 and 6, inclusive. In some embodiments, R³ is alkoxymethylsubstituted with an imaging moiety. In some embodiments, R³ is—CH₂OCH₂F, —CH₂OCH₂CH₂F, —CH₂OCH₂CH₂CH₂F, or —CH₂OCH₂CH₂CH₂CH₂CH₂F.

In some embodiments, R³ is selected from the group consisting ofhalogen; alkoxy, optionally substituted; C₁₋₆alkyl, optionallysubstituted; —CN; and —OH. In some embodiments, R³ is selected from thegroup consisting of fluorine, chlorine, bromine, iodine, —CF₃, OCH₃,—OH, —CH₃, and —CN.

In some embodiments, R³ is halogen. In some embodiments, R³ is fluorine.In some embodiments, R³ is chlorine. In some embodiments, R³ is bromine.In some embodiments, R³ is iodine. In some embodiments, R³ is —CF₃. Insome embodiments, R³ is alkoxy. In some embodiments, R³ is substitutedalkoxy. In some embodiments, R³ is —OCH₃. In some embodiments, R³ is—OH. In some embodiments, R³ is C₁₋₆alkyl. In some embodiments, R³ is—CH₃. In some embodiments, R³ is —CN. Additional examples of R³ groupswhich may be used in connection with a compound of Formula (IIa) aredescribed below in connection with a compound of Formula (IV).

Each of the R³ groups described herein in connection with a compound ofFormula (IIa) may be combined with any R⁴ group described herein, forexample, in connection with a compound of Formula (IIa) or (IV), and/orany suitable R¹ and/or L group as described herein, for example, inconnection with a compound of Formula (Ia)-(Id).

As described above, for a compound of Formula (IIa), each of R²-R⁶ isindependently hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,—OR^(A1), —N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1),—C(═O)SR^(A1), —C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1),—OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2),—NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂,—SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂,—C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1),—C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1),—OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂; orany two adjacent R²-R⁶ are joined to form an optionally substituted orunsubstituted carbocyclic, heterocyclic, aryl, or heteroaryl ring.

In some embodiments, each of R², R³, R⁵, and R⁶ are hydrogen. In someembodiments, R², R⁵, and R⁶ are all hydrogen. In some embodiments, R²and R⁶ are both hydrogen. In some embodiments, R³ is hydrogen. In someembodiments, at least one, two, three, or four of R², R³, R⁵, and R⁶ isnot hydrogen. In some embodiments, at least one of R², R³, R⁵, and R⁶ isnot hydrogen. In some embodiments, at least two of R², R³, R⁵, and R⁶are not hydrogen. In some embodiments, R² and R⁶ are hydrogen, and atleast one of R³, R⁴ and R⁵ is not hydrogen. In some embodiments, R², R⁵and R⁶ are hydrogen, and R³ and R⁴ are not hydrogen. In someembodiments, R², R⁵ and R⁶ are hydrogen, R³ and R⁴ are not hydrogen, andat least one of R³ and R⁴ is substituted with an imaging moiety. In someembodiments, R², R⁵ and R⁶ are hydrogen, R³ and R⁴ are not hydrogen, andat least one of R³ and R⁴ is an imaging moiety.

In some embodiments, one, two, three, four, five, six, seven, or eightof the following a)-h) apply for a provided compound of Formula (IIa),where suitable:

-   -   a) R¹ is substituted with an imaging moiety selected from the        group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is an imaging        moiety selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,        and ¹³¹I;    -   b) R⁴ is substituted with an imaging moiety selected from the        group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is an imaging        moiety selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,        and ¹³¹I;    -   c) L is selected from the group consisting of a bond;        substituted or unsubstituted, cyclic or acyclic C₁₋₆alkylene;        unsubstituted, acyclic C₁₋₆alkylene; acyclic C₁₋₆alkylene;        substituted or unsubstituted, cyclic or acyclic C₁₋₆alkenylene;        and substituted or unsubstituted, cyclic or acyclic        heteroaliphatic;    -   d) R¹ is selected from the group consisting of —N(R^(A))₂,        heteroaryl, heterocyclic, —C(═NH)NH₂, —NHC(═NH)NH₂,        —NR^(A)C(═NR^(A))N(R^(A))₂; —NHC(═NH)NHR^(A), and        —NHC(═NH)N(R^(A))₂, wherein R^(A) is as described herein;    -   e) R⁴ is selected from the group consisting of C₁₋₆alkyl,        alkoxy, and alkoxyalkyl, each optionally substituted with an        imaging moiety;    -   f) R³ is selected from the group consisting of halogen;        optionally substituted alkoxy; optionally substituted C₁₋₆alkyl;        —CN; and —OH;    -   g) R² is hydrogen;    -   h) R⁶ is hydrogen or halogen.

In some embodiments, a compound is provided comprising Formula (IIb):

wherein

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is selected from the group consisting of:

wherein each occurrence of R^(B) is independently hydrogen, substitutedor unsubstituted alkyl, or a nitrogen-protecting group, provided atleast two R^(B) are hydrogen;

R² and R⁶ are hydrogen;

each of R³, R⁴ and R⁵ is independently hydrogen, halogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —OR^(A1), —N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1),—C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂, —OC(═O)R^(A1),—OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2),—NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂,—SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂,—C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1),—C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1),—OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂; orany two adjacent R³, R⁴ and R⁵ are joined to form an optionallysubstituted or unsubstituted carbocyclic, heterocyclic, aryl, orheteroaryl ring;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; and

wherein R⁴ is substituted with an imaging moiety selected from the groupconsisting of ¹⁸F, ⁷⁶Br, and ¹²⁴I; or is associated with an imagingmoiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr, ^(99m)Tc, and¹¹¹In through a chelator; or is ¹²⁴I; or a salt thereof;

provided that if one of R³ or R⁵ is Cl, Br, or CF₃, then the other of R³or R⁵ is not H. In some embodiments, the compound is not of the formula:

For a compound of Formula (IIb), any suitable R¹, R², R³, R⁴, R⁵, R⁶,and/or L groups as described herein, for example, in connection with acompound of Formula (IIa) may be employed. In some embodiments, for acompound of Formula (IIb), R¹ is:

wherein each occurrence of R^(B) is independently hydrogen, substitutedor unsubstituted alkyl, or a nitrogen-protecting group, provided atleast two R^(B) are hydrogen. In some embodiments, for a compound ofFormula (IIb), R⁴ is:

In some embodiments, a compound of Formula (IIa) comprises Formula(III):

wherein

L is a bond; substituted or unsubstituted alkylene; substituted orunsubstituted alkenylene; or substituted or unsubstitutedheteroalkylene;

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

R³ is hydrogen, halogen, optionally substituted alkyl, —OR^(A1),—N(R^(A2))₂, —C(═O)R^(A1), —C(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), or—CN;

R⁴ is hydrogen, halogen, optionally substituted alkyl, —OR^(A1),—N(R^(A2))₂, —C(═O)R^(A1), —C(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), or—CN;

each occurrence of R^(A1) is independently hydrogen, or optionallysubstituted alkyl; and each occurrence of R^(A2) is independentlyhydrogen or optionally substituted alkyl, or two R^(A2) groups arejoined to form an optionally substituted heterocyclic ring; and

one or more of R³ and R⁴ and is substituted with an imaging moietyselected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or isassociated with an imaging moiety selected from the group consisting of⁶⁴Cu, ⁸⁹Zr, ^(99m)Tc, and ¹¹¹In through a chelator; or is ¹⁸F, ⁷⁶Br,¹²⁴I, and ¹³¹I; or a salt thereof.

In some cases, R⁴ is substituted with an imaging moiety selected fromthe group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is associated withan imaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator; or is ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I.In some cases, R³ is substituted with an imaging moiety selected fromthe group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is associated withan imaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator; or is ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I.

The compound of Formula (III) may comprise any suitable R³ and/or R⁴group(s) as described herein, for example, in connection with a compoundof Formula (IIa) or (IV), and/or any L and/or R¹ group as describedherein, for example, in connection with a compound of Formula (Ia)-(Id).

In some embodiments, a compound of Formula (III) comprises thestructure:

or salt thereof, wherein R⁴ and R³ may be any suitable R⁴ and R³ groupas described herein, for example, in connection with a compound ofFormula (IIa) or Formula (IV). In some embodiments, a compound ofFormula (III) comprises the structure:

wherein n is an integer between 1 and 6, inclusive; and I_(m) is animaging moiety selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,and ¹³¹I. In some embodiments, a compound of Formula (III) comprises thestructure:

wherein m is an integer between 1 and 6, inclusive; and I_(m) is animaging moiety selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,and ¹³¹I. In some embodiments, a compound of Formula (III) comprises thestructure:

wherein n is an integer between 1 and 6, inclusive; and I_(m) is animaging moiety selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,and ¹³¹I. R³ and R⁴ may be any suitable R³ and R⁴ as described herein,for example, in connection with a compound of Formula (IIa) or Formula(IV). In some embodiments, a compound of Formula (III) comprises thestructure:

wherein m is an integer between 1 and 6, inclusive; and I_(m) is animaging moiety selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,and ¹³¹I. R³ and R⁴ may be any suitable R³ and R⁴ as described herein,for example, in connection with a compound of Formula (IIa) or Formula(IV). In some embodiments, a compound of Formula (III) comprises thestructure:

wherein n is an integer between 1 and 6, inclusive; and I_(m) is animaging moiety selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,and ¹³¹I. In some embodiments, a compound of Formula (III) comprises thestructure:

wherein m is an integer between 1 and 6, inclusive; and I_(m) is animaging moiety selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,and ¹³¹I. In some embodiments, a compound of Formula (III) comprises thestructure:

wherein n is an integer between 1 and 6, inclusive; and I_(m) is animaging moiety selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,and ¹³¹I. R¹ may be any suitable R¹ as described herein, for example, inconnection with a compound of Formula (Ia)-(Id). In some embodiments, acompound of Formula (III) comprises the structure:

wherein m is an integer between 1 and 6, inclusive; and I_(m) is animaging moiety selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,and ¹³¹I. R¹ may be any suitable R¹ as described herein, for example, inconnection with a compound of Formula (Ia)-(Id). In some embodiments, acompound of Formula (III) comprises the structure:

wherein n is an integer between 1 and 6, inclusive; and I_(m) is animaging moiety selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,and ¹³¹I. R¹ may be any suitable R¹ as described herein, for example, inconnection with a compound of Formula (Ia)-(Id). In some embodiments, acompound of Formula (III) comprises the structure:

wherein m is an integer between 1 and 6, inclusive; and I_(m) is animaging moiety selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,and ¹³¹I. R¹ may be any suitable R¹ as described herein, for example, inconnection with a compound of Formula (Ia)-(Id). In some embodiments, acompound of Formula (III) comprises the structure:

wherein m is an integer between 1 and 6, inclusive; and I_(m) is animaging moiety selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,and ¹³¹I. L and/or R¹ may be any suitable L and/or R¹ as describedherein, for example, in connection with a compound of Formula (Ia)-(Id).In some embodiments, a compound of Formula (III) comprises thestructure:

L and/or R¹ may be any suitable L and/or R¹ as described in connectionwith a compound of Formula (Ia)-(Id) and/or R⁴ may be any suitable R⁴ asdescribed herein, for example, in connection with a compound of Formula(IIa) or Formula (IV). In some embodiments, a compound of Formula (III)comprises the structure:

L and/or R¹ may be any suitable L and/or R¹ as described herein, forexample, in connection with a compound of Formula (Ia)-(Id) and/or R⁴may be any suitable R⁴ as described in connection with a compound ofFormula (IIa) or Formula (IV). In some embodiments, a compound ofFormula (III) comprises the structure:

L and/or R¹ may be any suitable L and/or R¹ as described herein, forexample, in connection with a compound of Formula (Ia)-(Id) and/or R⁴may be any suitable R⁴ as described in connection with a compound ofFormula (IIa) or Formula (IV).

In some embodiments, a compound of Formula (III comprises Formula (IV):

wherein

L is a bond; substituted or unsubstituted alkylene; substituted orunsubstituted alkenylene; or substituted or unsubstitutedheteroalkylene;

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

R³ is halogen, optionally substituted alkyl, —OR^(A1), —N(R^(A2))₂,—C(═O)R^(A1), —C(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), or —CN;

R⁴ is hydrogen, halogen, optionally substituted alkyl, —OR^(A1),—N(R^(A2))₂, —C(═O)R^(A1), —C(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), or—CN;

R⁵ is halogen, optionally substituted alkyl, —OR^(A1), —N(R^(A2))₂,—C(═O)R^(A1), —C(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), or —CN;

each occurrence of R^(A1) is independently hydrogen, or optionallysubstituted alkyl; and each occurrence of R^(A2) is independentlyhydrogen or optionally substituted alkyl, or two R^(A2) groups arejoined to form an optionally substituted heterocyclic ring; and

one or more of R³ and R⁴ is substituted with an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is associatedwith an imaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator; or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or a saltthereof.

The compound of Formula (IV) may comprise any suitable R³ and/or R⁴ asdescribed herein, for example, in connection with a compound of Formula(IIa), and/or any L and/or R¹ group as described herein, for example, inconnection with a compound of Formula (Ia)-(Id). In certain embodiments,the imaging moiety is ¹⁸F. In certain embodiments, the imaging moiety is⁷⁶Br. In certain embodiments, the imaging moiety is ¹²⁴I. In certainembodiments, the imaging moiety is ¹³¹I. In some cases, the imagingmoiety is not ¹³¹I. In some cases, the imaging moiety is ¹⁸F, ⁷⁶Br, or¹²⁴I. In some cases, the imaging moiety is ¹⁸F or ⁷⁶Br.

In some embodiments, in a compound of Formula (IV), both R³ and R⁵ arenot —OH.

In some embodiments, L is a bond. In some embodiments, L is —CH₂—. Insome embodiments, L is —CH═CH—. Other suitable L groups are described inconnection with a compound of Formula (Ia)-(Id).

The following description of R³ groups may be used in connection with acompound of Formula (IV), or as noted herein. In some embodiments, R³ ishalogen, optionally substituted alkyl, —OR^(A1), —N(R^(A2))₂,—C(═O)R^(A1), —C(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), or —CN. In someembodiments, R³ is hydrogen, halogen, optionally substituted alkyl,—OR^(A1), or —CN. In some embodiments, R³ is hydrogen, fluoro, bromo,chloro, iodo, trifluoromethyl, methoxy, hydroxyl, or —CN. In someembodiments, R³ is not hydroxyl. In some embodiments, R³ is not iodo,bromo, chloro, or fluoro. In some embodiments, R³ is fluoro. In someembodiments, R³ is ¹⁸F. In some embodiments, R³ is alkyl substitutedwith an imaging moiety. In some embodiments, R³ is alkoxyalkylsubstituted with an imaging moiety. In some embodiments, R³ isalkoxymethyl substituted with an imaging moiety. In some embodiments, R³is alkoxyethyl substituted with an imaging moiety. In some embodiments,R³ is alkoxypropyl substituted with an imaging moiety.

In some embodiments, R³ is selected from the group consisting of:

wherein m and n is an integer between 1 and 6, inclusive; and I_(m) isan imaging moiety. In some embodiments, R³ is selected from the groupconsisting of:

wherein I_(m) is an imaging moiety. In some embodiments, R is selectedfrom the group consisting of:

wherein m and n is an integer between 1 and 6, inclusive. In someembodiments, R³ is selected from the group consisting of:

In some embodiments, R³ is:

wherein m is an integer between 1 and 6, inclusive; and I_(m) is animaging moiety. In some embodiments, R³ is:

wherein m is an integer between 1 and 6, inclusive. In some embodiments,R³ is:

wherein I_(m) is an imaging moiety. In some embodiments, R³ is:

In some embodiments, R³ is:

wherein I_(m) is an imaging moiety. In some embodiments, R³ is:

In some cases, R³ is —(CH₂)₄I_(m), —(CH₂)₅I_(m), —(CH₂)₆I_(m),—(CH₂)₇I_(m), —(CH₂)₈I_(m), —(CH₂)₉I_(m), or —(CH₂)₁₀I_(m). In somecases, R³ is —(CH₂)₄ ¹⁸F, —(CH₂)₅ ¹⁸F, —(CH₂)₆ ¹⁸F, —(CH₂)₇ ¹⁸F, —(CH₂)₈¹⁸F, —(CH₂)₉ ¹⁸F, or —(CH₂)₁₀ ¹⁸F. In some embodiments, R³ is:

wherein n is an integer between 1 and 6, inclusive; and I_(m) is animaging moiety. In some embodiments, R³ is:

wherein n is an integer between 1 and 6, inclusive. In some embodiments,R³ is:

wherein I_(m) is an imaging moiety. In some embodiments, R³ is:

In some embodiments, R³ is:

wherein I_(m) is an imaging moiety. In some embodiments, R³ is:

In some embodiments R³ is:

wherein I_(m) is an imaging moiety. In some embodiments, R³ is:

In some cases, R³ is —O(CH₂)₅I_(m), —O(CH₂)₆I_(m), —O(CH₂)₇I_(m),—O(CH₂)₈I_(m), —O(CH₂)₉I_(m), or —O(CH₂)₁₀I_(m). In some cases, R³ is—O(CH₂)₅ ¹⁸F, —O(CH₂)₆ ¹⁸F, —O(CH₂)₇ ¹⁸F, —O(CH₂)₈ ¹⁸F, —O(CH₂)₉ ¹⁸F, or—O(CH₂)₁₀ ¹⁸F. In some embodiments, R³ is:

wherein n is an integer between 1 and 6, inclusive; and I_(m) is animaging moiety. In some embodiments, R³ is:

wherein n is an integer between 1 and 6, inclusive. In some embodiments,R³ is:

wherein I_(m) is an imaging moiety. In some embodiments, R³ is:

In some cases, R³ is —CH₂O(CH₂)₃I_(m), —CH₂O(CH₂)₄I_(m),CH₂O(CH₂)₅I_(m), —CH₂O(CH₂)₆I_(m), —CH₂O(CH₂)₇I_(m), —CH₂O(CH₂)₈I_(m),—CH₂O(CH₂)₉I_(m), or —CH₂O(CH₂)₁₀I_(m). In some cases, R³ is —CH₂O(CH₂)₃¹⁸F, —CH₂O(CH₂)₄ ¹⁸F, —CH₂O(CH₂)₅ ¹⁸F, —CH₂O(CH₂)₆ ¹⁸F, —CH₂O(CH₂)₇ ¹⁸F,—CH₂O(CH₂)₈ ¹⁸F, —CH₂O(CH₂)₉ ¹⁸F, or —CH₂O(CH₂)₁₀ ¹⁸F.

In the above embodiments wherein R³ is described in connection with acompound of Formula (IV), the compound of Formula (III) may comprise anysuitable R⁴ group as described in connection with a compound of Formula(IIa), and/or any L and/or R¹ group as described in connection with acompound of Formula (Ia)-(Id).

The following description of R⁴ groups may be used in connection with acompound of Formula (IV), or as noted herein. In some embodiments, R⁴ ishydrogen, halogen, optionally substituted alkyl, —OR^(A1), or—NR^(A2)C(═O)R^(A2). In some embodiments, R⁴ is fluoro. In someembodiments, R⁴ is ¹⁸F. In some embodiments, R⁴ is alkyl substitutedwith an imaging moiety. In some embodiments, R⁴ is alkoxy substitutedwith an imaging moiety. In some embodiments, R⁴ is alkoxyalkylsubstituted with an imaging moiety. In some embodiments, R⁴ isalkoxymethyl substituted with an imaging moiety. In some embodiments, R⁴is alkoxyethyl substituted with an imaging moiety. In some embodiments,R⁴ is alkoxypropyl substituted with an imaging moiety. In certainembodiments, the imaging moiety is ¹⁸F.

In some embodiments, R⁴ is selected from the group consisting of:

wherein m is an integer between 1 and 6, inclusive; and I_(m) is animaging moiety. In some embodiments, R⁴ is selected from the groupconsisting of:

wherein I_(m) is an imaging moiety. In some embodiments, R⁴ is selectedfrom the group consisting of:

wherein m or n is an integer between 1 and 6, inclusive. In someembodiments, R⁴ is selected from the group consisting of:

In some embodiments, R⁴ is:

wherein m is an integer between 1 and 6, inclusive; and I_(m) is animaging moiety. In some embodiments, R⁴ is:

wherein m is an integer between 1 and 6, inclusive. In some embodiments,R⁴ is:

wherein I_(m) is an imaging moiety. In some embodiments, R⁴ is:

In some embodiments, R⁴ is:

wherein I_(m) is an imaging moiety. In some embodiments, R⁴ is:

In some cases, R⁴ is —(CH₂)₄I_(m), —(CH₂)₅I_(m), —(CH₂)₆I_(m),—(CH₂)₇I_(m), —(CH₂)₈I_(m), —(CH₂)₉I_(m), or —(CH₂)₁₀I_(m). In somecases, R⁴ is —(CH₂)₄ ¹⁸F, —(CH₂)₅ ¹⁸F, —(CH₂)₆ ¹⁸F, —(CH₂)₇ ¹⁸F, —(CH₂)₈¹⁸F, —(CH₂)₉ ¹⁸F, or —(CH₂)₁₀ ¹⁸F. In some embodiments, R⁴ is:

wherein n is an integer between 1 and 6, inclusive; and I_(m) is animaging moiety. In some embodiments, R⁴ is:

wherein n is an integer between 1 and 6, inclusive. In some embodiments,R⁴ is:

wherein I_(m) is an imaging moiety. In some embodiments, R⁴ is:

In some embodiments, R⁴ is:

wherein I_(m) is an imaging moiety. In some embodiments, R⁴ is:

In some embodiments, R⁴ is:

wherein I_(m) is an imaging moiety. In some embodiments, R⁴ is:

In some cases, R⁴ is —O(CH₂)₅I_(m), —O(CH₂)₆I_(m), —O(CH₂)₇I_(m),—O(CH₂)₈I_(m), —O(CH₂)₉I_(m), or —O(CH₂)₁₀I_(m). In some cases, R⁴ is—O(CH₂)₅ ¹⁸F, —O(CH₂)₆ ¹⁸F, —O(CH₂)₇ ¹⁸F, —O(CH₂)₈ ¹⁸F, —O(CH₂)₉ ¹⁸F, or—O(CH₂)₁₀ ¹⁸F. In some embodiments, R⁴ is:

wherein n is an integer between 1 and 6, inclusive; and I_(m) is animaging moiety. In some embodiments, R⁴ is:

wherein n is an integer between 1 and 6, inclusive. In some embodiments,R⁴ is:

wherein I_(m) is an imaging moiety. In some embodiments, R⁴ is:

In some cases, R⁴ is —CH₂O(CH₂)₃I_(m), —CH₂O(CH₂)₄I_(m),CH₂O(CH₂)₅I_(m), —CH₂O(CH₂)₆I_(m), —CH₂O(CH₂)₇I_(m), —CH₂O(CH₂)₈I_(m),—CH₂O(CH₂)₉I_(m), or —CH₂O(CH₂)₁₀I_(m). In some cases, R⁴ is —CH₂O(CH₂)₃¹⁸F, —CH₂O(CH₂)₄ ¹⁸F, —CH₂O(CH₂)₅ ¹⁸F, —CH₂O(CH₂)₆ ¹⁸F, —CH₂O(CH₂)₇ ¹⁸F,—CH₂O(CH₂)₈ ¹⁸F, —CH₂O(CH₂)₉ ¹⁸F, or —CH₂O(CH₂)₁₀ ¹⁸F.

In the above embodiments wherein R⁴ is described in connection with acompound of Formula (IV), the compound of Formula (III) may comprise anysuitable R³ as described herein, for example, in connection with acompound of Formula (IIa) or (IV), and/or any L and/or R¹ group asdescribed herein, for example, in connection with a compound of Formula(Ia)-(Id).

The following description of R¹ groups may be used in connection with acompound of Formula (IV), or as noted herein. In some embodiments, R¹ isselected from the group consisting of:

—NH₂, —NHCH₃, —NHCH₂CH₃, and —NHCH₂CH₂CH₃. In some embodiments, R is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is —NH₂, —NHCH₃, —NHCH₂CH₃, or —NHCH₂CH₂CH₃. Insome embodiments, R³ is hydrogen, fluoro, bromo, chloro, iodo,trifluoromethyl, methoxy, hydroxyl, or —CN; and R⁴ is alkyl substitutedwith an imaging moiety, alkoxy substituted with an imaging moiety, oralkoxyalkyl substituted with an imaging moiety.

In the above embodiments wherein R¹ is described in connection with acompound of Formula (IV), the compound of Formula (III) may comprise anysuitable R³ and/or R⁴ as described herein, for example, in connectionwith a compound of Formula (IIa) or (IV), and/or any L group asdescribed herein, for example, in connection with a compound of Formula(Ia)-(Id).

As noted above, for a compound of Formula (IV), any suitable combinationof R¹, R³, R⁴, R⁵, and L groups may be used as described herein. Forexample, wherein R¹ is as described in connection with a compound ofFormula (IV) or (Ia)-(Id), R³ and/or R⁴ is as described in connectionwith a compound of Formula (IIa) or (IV), and/or L is as described inconnection with a compound of Formula (Ia)-(Id).

In some embodiments, for a compound of Formula (IV), L is —CH₂—, and R¹is:

R³ is halogen; and R⁴ is alkoxyalkyl substituted with an imaging moiety.

In some embodiments, a compound is provided comprising Formula(Va)-(Vd):

wherein

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

R² is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR_(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

R³ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

each occurrence of R⁴ is independently hydrogen, halogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —OR^(A1), —N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1),—C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂, —OC(═O)R^(A1),—OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2),—NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂,—SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂,—C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1),—C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1),—OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring;

p is 0, 1, or 2; and

r is 0, 1, 2, 3, or 4;

at least one R⁴ is substituted with an imaging moiety selected from thegroup consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is associated with animaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator; or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or a saltthereof.

In some embodiments, a compound is provided comprising Formula(Va)-(Vd):

wherein

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

R² is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

R³ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

each occurrence of R⁴ is independently hydrogen, halogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —OR^(A1), —N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1),—C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂, —OC(═O)R^(A1),—OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2),—NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂,—SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂,—C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1),—C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1),—OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring;

at least one R⁴ is substituted with an imaging moiety selected from thegroup consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is associated with animaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator; or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or a saltthereof.

For a compound of Formula (Va)-(Vd), any suitable combination of R¹, R²,R³, R⁴, and L groups may be used as described herein. For example,wherein R¹ is as described in connection with a compound of Formula (IV)or (Ia)-(Id), R³ and/or R⁴ is as described in connection with a compoundof Formula (IIa) or (IV), and/or L is as described in connection with acompound of Formula (Ia)-(Id). In certain embodiments, the imagingmoiety is ¹⁸F. In certain embodiments, the imaging moiety is ⁷⁶Br. Incertain embodiments, the imaging moiety is ¹²⁴I. In certain embodiments,the imaging moiety is ¹³¹I. In some cases, the imaging moiety is not¹³¹I. In some cases, the imaging moiety is ¹⁸F, ⁷⁶Br, or ¹²⁴I. In somecases, the imaging moiety is ¹⁸F or ⁷⁶Br.

In some cases, a compound of Formula (Va)-(Vd) comprises the structure:

wherein R¹, R², R³, R⁴, and L are as described herein. For example,wherein R¹ is as described in connection with a compound of Formula (IV)or (Ia)-(Id), R³ and/or R⁴ is as described in connection with a compoundof Formula (IIa) or (IV), and/or L is as described in connection with acompound of Formula (Ia)-(Id). In some cases, a compound of Formula(Va)-(Vd) comprises the structure:

In some cases, a compound of Formula (Va)-(Vd) comprises the structure:

In some cases, a compound of Formula (Va)-(Vd) comprises the structure:

In some cases, a compound of Formula (Va)-(Vd) comprises the structure:

In some cases, a compound of Formula (Va)-(Vd) comprises the structure:

In some cases, a compound of Formula (Va)-(Vd) comprises the structure:

In some cases, a compound of Formula (Va)-(Vd) comprises the structure:

In some cases, a compound of Formula (Va)-(Vd) comprises the structure:

In some cases, a compound of Formula (Va)-(Vd) comprises the structure:

In some cases, a compound of Formula (Va)-(Vd) comprises the structure:

In some embodiments, a compound is provided comprising Formula (VI):

wherein

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

R² is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

R³ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

R⁴ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

R⁴ is substituted with an imaging moiety selected from the groupconsisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is associated with animaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator; or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; or a salt thereof.

For a compound of Formula (VI), any suitable combination of R¹, R², R³,R⁴, and L groups may be used as described herein. For example, whereinR¹ is as described in connection with a compound of Formula (IV) or(Ia)-(Id), R³ and/or R⁴ is as described in connection with a compound ofFormula (IIa) or (IV), and/or L is as described in connection with acompound of Formula (Ia)-(Id). In some cases, R² is halogen. In certainembodiments, the imaging moiety is ¹⁸F. In certain embodiments, theimaging moiety is ⁷⁶Br. In certain embodiments, the imaging moiety is¹²⁴I. In certain embodiments, the imaging moiety is ¹³¹I. In some cases,the imaging moiety is not ¹³¹I. In some cases, the imaging moiety is¹⁸F, ⁷⁶Br, or ¹²⁴I. In some cases, the imaging moiety is ¹⁸F or ⁷⁶Br.

In some embodiments, a compound of Formula (VI) comprises the structure:

wherein R¹, R⁴, and L are as described herein. For example, wherein R¹is as described in connection with a compound of Formula (IV) or(Ia)-(Id), R⁴ is as described in connection with a compound of Formula(IIa) or (IV), and/or L is as described in connection with a compound ofFormula (Ia)-(Id). In some embodiments, a compound of Formula (VI) hasthe structure:

In some embodiments, a compound of Formula (VI) comprises the structure:

In some embodiments, a compound of Formula (VI) comprises the structure:

In some embodiments, a compound of Formula (VI) comprises the structure:

In some embodiments, a compound of Formula (VI) comprises the structure:

In some embodiments, a compound is provided comprising the formula:

wherein

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

R² is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

R³ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

R⁴ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

wherein R⁴ is substituted with an imaging moiety selected from the groupconsisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is associated with animaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator; or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I;

wherein p and q are independently 0, 1, 2, 3, or 4.

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; or a salt thereof.

In some embodiments, a compound is provided comprising Formula (VII):

wherein

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

R² is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

R³ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

R⁴ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

wherein R⁴ is substituted with an imaging moiety selected from the groupconsisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or is associated with animaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator; or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; or a salt thereof.

For a compound of Formula (VII), any suitable combination of R¹, R², R³,R⁴, and L groups may be used as described herein. For example, whereinR¹ is as described in connection with a compound of Formula (IV) or(Ia)-(Id), R³ and/or R⁴ is as described in connection with a compound ofFormula (IIa) or (IV), and/or L is as described in connection with acompound of Formula (Ia)-(Id). In certain embodiments, the imagingmoiety is ¹⁸F. In certain embodiments, the imaging moiety is ⁷⁶Br. Incertain embodiments, the imaging moiety is ¹²⁴I. In certain embodiments,the imaging moiety is ¹³¹I. In some cases, the imaging moiety is not¹³¹I. In some cases, the imaging moiety is ¹⁸F, ⁷⁶Br, or ¹²⁴I. In somecases, the imaging moiety is ¹⁸F or ⁷⁶Br.

In some embodiments, a compound of Formula (VII) comprises thestructure:

wherein R¹, R⁴, and L are as described herein. For example, wherein R¹is as described in connection with a compound of Formula (IV) or(Ia)-(Id), and/or is as described in connection with a compound ofFormula (IIa) or (IV), and/or L is as described in connection with acompound of Formula (Ia)-(Id). The above compounds may optionally besubstituted with R² and/or R³ (e.g., as described for Formula (VII)).

In some embodiments, a compound of Formula (VII) comprises thestructure:

wherein R¹, R⁴, and L are as described herein. For example, wherein R¹is as described in connection with a compound of Formula (IV) or(Ia)-(Id), R⁴ is as described in connection with a compound of Formula(IIa) or (IV), and/or L is as described in connection with a compound ofFormula (Ia)-(Id).

In some embodiments, one or more of L, R¹, R², R³, R⁴, R⁵, and R⁶ of acompound of Formula (Ia)-(Id), (IIa)-(IIb), (III), (IV), (Va)-(Vd),(VI), or (VII) are selected from Table A. In certain embodiments, L orR¹ of a compound of Formula (Ia), (Ib), (Ic), or (Id) is selected fromTable A. In certain embodiments, L and R¹ of a compound of Formula (Ia),(Ib), (Ic), or (Id) are selected from Table A. In some embodiments, oneof L, R¹, R², R³, R⁴, R⁵, and R⁶ of a compound of Formula (IIa) or (IIb)is selected from Table A. In certain embodiments, two, three, four,five, six, or all of L, R¹, R², R³, R⁴, R⁵, and R⁶ of a compound ofFormula (IIa) or (IIb) are selected from Table A. In some embodiments,one of L, R¹, R³, and R⁴ of a compound of Formula (III) is selected fromTable A. In certain embodiments, two, three, or all of L, R¹, R³, and R⁴of a compound of Formula (III) are selected from Table A. In someembodiments, one of L, R¹, R³, R⁴, and R⁵ of a compound of Formula (IV)is selected from Table A. In certain embodiments, two, three, four, orall of L, R¹, R³, R⁴, and R⁵ of a compound of Formula (IV) are selectedfrom Table A. In some embodiments, one of L, R¹, R², R³, and R⁴ of acompound of Formula (Va), (Vb), (Vc), (Vd), (VI), or (VII) is selectedfrom Table A. In certain embodiments, two, three, four, or all of L, R¹,R², R³, and R⁴ of a compound of Formula (Va), (Vb), (Vc), (Vd), (VI), or(VII) are selected from Table A.

TABLE A L R¹ R² R³ R⁴ R⁵ R⁶ bond —NH₂ —H —H —H —H —H —CH₂— —NHCH₃ —Br—OCH₂CH₂F —Br —F —CH₂CH₂— —NHCH₂CH₃ —CF₃ —OCH₂CH₂ ¹⁸F —CF₃ —CH₂CH₂CH₂——NHCH₂CH₂CH₃ —O(CH₂)₂F —OCH₂CH₂Im —O(CH₂)₂F —(CH₂)₄—

—O(CH₂)₂ ¹⁸F —¹⁸F —O(CH₂)₂ ¹⁸F —CH(CH₃)—

—O(CH₂)₂Im —Im —O(CH₂)₂Im —CH₂O—

—OH —CH₂ ¹⁸F —OH —CH₂CH₂O—

—Cl —CH₂Im —Cl —(CH₂)₃O—

—I —CH₂O(CH₂)₄ ¹⁸F —I —OCH₂—

—CH₃ —CH₂O(CH₂)₄Im —CH₃ —OCH₂CH₂—

—CN —CH₂CH₂ ¹⁸F —CN —O(CH₂)₃—

—OCH₃ —CH₂CH₂Im —OCH₃

—CH₂CH₃

—CH₂CH₂CH₂ ¹⁸F

—CH₂CH₂CH₂Im —CH(CH₃)CH₂—

—OH —CH₂CH(CH₃)—

—Br —CH═CH—

—O(CH₂)₃ ¹⁸F

—O(CH₂)₃Im —CH═N—

—(CH₂)₄ ¹⁸F —NHCH₂CH₂—

—(CH₂)₄Im

—O(CH₂)₄ ¹⁸F

—O(CH₂)₄Im

—OCH₂ ¹⁸F

—OCH₂Im

In some cases, a compound is provided of comprising the formula:

wherein

R⁹ and R¹⁰ are independently selected from the group consisting of H,—OR¹¹, F, Cl, Br, I, —CF₃, alkyl(C₁-C₄), and imaging moiety (I_(m));

R¹¹, R¹² and R¹³ are selected from the group consisting of H, alkyl, andaryl; and

W and X are independently selected from the group consisting of H, —OR₄,—N(R¹¹)₂, F, Cl, Br, —CF₃, I_(m), aryl, and heteroaryl;

wherein A) Y and Z are independently selected from the group consistingof —CH—, —CH₂—, —O—, —N—, —NR¹¹—, and —CH═CH— when a linking group Qbetween Y and Z is present or absent, wherein Q is selected from thegroup consisting of —CH—, —CH₂—, —CR¹¹—, —N—, —NH—, —NR¹¹—, —O—, and—S—; or

B) Y and Z are independently selected from the group consisting of H,—OR₄, —N(R¹¹)₂, F, Cl, Br, —CF₃, I_(m), aryl, and heteroaryl whenlinking group Q is absent;

wherein I_(m) is selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,and ¹³¹I, and is present in either W—Z or R⁹-R¹³; or a salt thereof,provided the compound is not of the formula:

In some cases, a compound is provided comprising the formula:

wherein R⁹ is independently selected from the group consisting of H,—CF₃, and alkyl(C₁-C₄);

W, Y and Z are independently selected from the group consisting of H,—OR¹¹, N(R¹¹)₂, F, Cl, Br, —CF₃, I_(m), aryl and heteroaryl; and

R¹¹ is selected from the group consisting of H, alkyl, and aryl;

wherein I_(m) is selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,and ¹³¹I, and is present in either W, Y, Z, R⁹, or R¹¹; or a saltthereof;

provided the compound is not of the formula:

In some cases, a compound is provided comprising the formula:

wherein W and Y are independently selected from the group consisting ofH, —OR¹¹, F, Cl, Br, —CF₃, and I_(m); and

R¹¹ is alkyl,

wherein I_(m) is selected from the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I,and ¹³¹I, and is present in either W, Y, or R¹¹; or a salt thereof;

provided the compound is not of the formula:

In some embodiments, a compound comprises the formula:

or a salt thereof, wherein each fluorine may optionally be enriched with18 and/or each Br may be optionally enriched with ⁷⁶Br. In someembodiments, only one I_(m) is present in the compound.

In some embodiments, a compound of the invention is not:

wherein each fluorine may optionally be enriched in ¹⁸F, and/or each Brmay be optionally enriched with ⁷⁶Br.

As used herein, the term “imaging agent” refers to any chemical compoundthat includes an imaging moiety. An “imaging moiety” refers to an atomor group of atoms that is capable of producing a detectable signalitself, or upon exposure to an external source of energy (e.g.,electromagnetic radiation, ultrasound, and the like). Non-limitingexamples of imaging moieties include ¹¹C, ¹³N, ¹⁸F, ⁷⁶Br, ¹²³I, ¹²⁴I,¹²⁵I, ¹³¹I, ^(99m)Tc, ⁹⁵Tc, ¹¹¹In, ⁶²Cu, ⁶⁴Cu, ⁶⁷Ga, and ⁶⁸Ga. In someembodiments, the imaging moiety is selected from the group consisting of¹⁸F, ⁷⁶Br, ¹²⁴I, ¹³¹I, ⁶⁴Cu, ⁸⁹Zr, ^(99m)Tc, and ¹¹¹In. In certainembodiments, the imaging moiety is directly associated (i.e., through acovalent bond) with a compound as described herein (e.g., in the case of¹⁸F, ⁷⁶Br, ¹²⁴I, or ¹³¹I). In other embodiments, the imaging moiety isassociated with the compound through a chelator (e.g., in the case of⁶⁴Cu, ⁸⁹Zr, ^(99m)Tc, and ¹¹¹In). Chelators are described in more detailherein. In certain embodiments, the imaging moiety is associated withthe compound through non-covalent interactions (e.g., electrostaticinteractions). In certain embodiments, the imaging moiety is ¹⁸F. Incertain embodiments, the imaging moiety is ⁷⁶Br. In certain embodiments,the imaging moiety is ¹²⁴I. In certain embodiments, the imaging moietyis ¹³¹I. In some cases, the imaging moiety is not ¹³¹I. In some cases,the imaging moiety is ¹⁸F, ⁷⁶Br, or ¹²⁴I. In some cases, the imagingmoiety is ¹⁸F or ⁷⁶Br. In some cases, an imaging agent comprises asingle imaging moiety. In some cases, an imaging agent comprises morethan one imaging moiety (e.g., two imaging moieties).

Imaging agents allow for the detection, imaging, and/or monitoring ofthe presence and/or progression of a condition, pathological disorder,and/or disease. Typically, the imaging agent may be administered to asubject in order to provide information relating to at least a portionof the subject (e.g., human). In some cases, an imaging agent may beused to highlight a specific area of a subject, rendering organs, bloodvessels, tissues, and/or other portions more detectable and more clearlyimaged. By increasing the detectability and/or image quality of the areabeing studied, the presence and extent of disease and/or injury can bedetermined.

In some embodiments, an imaging agent or composition thereof is enrichedwith an isotope such as a radioisotope. In such a case, the imagingagent or composition thereof may be referred to as being “isotopicallyenriched.” An “isotopically enriched” composition refers to acomposition comprising a percentage of one or more isotopes of anelement that is more than the percentage of that isotope that occursnaturally. For example, a composition that is isotopically enriched witha fluoride species may be “isotopically enriched” with fluorine-18(¹⁸F). Thus, with regard to a plurality of compounds, when a particularatomic position is designated as ¹⁸F, it is to be understood that theabundance (or frequency) of ¹⁸F at that position (in the plurality) isgreater than the natural abundance (or frequency) of ¹⁸F, which isessentially zero.

In some embodiments, an atom designated as being enriched may have aminimum isotopic enrichment factor of about 0.001% (i.e., about 1 out of10⁵ atoms is an enriched atom), 0.002%, 0.003%, 0.004%, 0.005%, 0.006%,0.007%, 0.008%, 0.009%, 0.01%, about 0.05%, about 0.1%, about 0.2%,about 0.3%, about 0.4%, about 0.5%, about 0.75%, about 1%, about 2%,about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%,about 95%, or greater. The minimum isotopic enrichment factor, in someinstances, may range from about 0.001% to about 1%. For example, inembodiments wherein the imaging moiety is fluorine, a fluorinedesignated as ¹⁸F may have a minimum isotopic enrichment factor of about0.001% (i.e., about 1 out of 10⁵ fluorine species is ¹⁸F), 0.002%,0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, about0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about0.75%, about 1%, about 2%, about 3%, about 4%, about 5%, about 10%,about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about70%, about 80%, about 90%, about 95%, or greater. The isotopicenrichment of the compounds provided herein can be determined usingconventional analytical methods known to one of ordinary skill in theart, including mass spectrometry and HPLC.

In some embodiments, compositions, methods, uses, and systems describedherein include or use compounds of Formula (Ia)-(Id), (IIa)-(IIb),(III), (IV), (Va)-(Vd), (VI), or (VII). In some embodiments, the presentinvention relates to methods of imaging, including methods of imaging asubject that includes administering a composition that includes animaging agent to the subject by injection, infusion, or any other knownmethod, and imaging a region of interest of the subject. Regions ofinterest may include, but are not limited to, the heart, a portion ofthe heart, cardiovascular system, cardiac vessels, pancreas, adrenalglands, salivary glands, thymus, or other organs with high sympatheticinnervation or high imaging agent uptake. Regions of interest may alsoinclude tumors. In certain embodiments, the imaging agent is used as aradiotracer for mapping the cardiac nerve terminal in vivo usingpositron emission tomography (PET) or other imaging techniques. An eventof interest can be imaged and detected and/or other information may bedetermined using methods and/or systems of the disclosure.

The imaging agents as described herein may act as norepinephrinetransporter ligands that target or bind NET. In some embodiments, themethods comprise detecting NET, including determining NET levels, in asubject, wherein determining may comprise determining the level,density, function, and/or localization of NET in a subject. In certainembodiments, without wishing to be bound by a particular theory, theimaging agent binds to norepinephrine transporters (NET) allowing forimaging of cardiac sympathetic innervation or activity. Accordingly, insome aspects, methods for assessing cardiac sympathetic innervationand/or myocardial sympathetic function are provided.

B. Chelators

In some cases, an imaging moiety may be associated with a compound asdescribed herein via association with a chelator (e.g., in embodimentswhere the imaging moiety is ⁶⁴Cu, ⁸⁹Zr, ^(99m)Tc, or ¹¹¹In). The termchelator is given its ordinary meaning in the art and generally refersto a chemical moiety capable of complexing an imaging moiety (e.g., ametal ion and/or radionuclide), wherein the complex is stable underphysiological conditions. For example, generally, the imaging moietyremains complexed with the chelator in vivo. In some embodiments, thechelator is the moiety or group on a compound that binds to an imagingmoiety through one or more donor atoms and/or groups. The chelator maybe any chelator known in the art for complexing a medically useful metalion or radionuclide. In some embodiments, the chelator comprises one,two, three, four, five, six, seven, eight, nine, or ten donor atomsand/or groups. In embodiments where the chelator comprises more than onedonor atom and/or group, the donor atoms/groups may be the same ordifferent. Non-limiting examples of donor atoms/groups include —OH, —O⁻,—COOR′, —COO⁻, —N(R′)₂, —SR′, —OPO₃ ⁻, or —OPO₃R′, wherein each R′ canbe the same of different and is hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl,alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl,heterocyclylalkyl, each optionally substituted. In some cases, thechelator may be a macrocycle. Non-limiting examples of chelators aredescribed in International PCT Publication No. WO2011/005322 and U.S.Pat. No. 6,511,648, each of which is incorporated herein by reference.In some embodiments, the chelator comprises diaminodithiol,mercaptoacetyltriglycine, monoaminomonoamide, picolylamine monoaceticacid, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid,bis(thiosemicarbazone), propyleneamine oxime, ethylenediaminetetraaceticacid, and diethylenetriaminepentaacetic acid.

In some cases, an imaging moiety associated with a chelator may befurther associated with one or more ancillary or co-ligands. “Ancillary”or “co-ligands” may be ligands which serve to complete the coordinationsphere of the imaging moiety together with the chelator. In someembodiments, the imaging moiety coordination sphere may comprise one ormore bonding atoms and/or groups form the chelators or bonding units andoptionally, one or more ancillary and/or co-ligands. Ancillary orco-ligands useful in the preparation of radiopharmaceuticals and indiagnostic kits useful for the preparation of said radiopharmaceuticalsmay be comprised of one or more oxygen, nitrogen, carbon, sulfur,phosphorus, arsenic, selenium, and tellurium donor atoms.

C. Imaging Agent Precursors

In another aspect of the invention, imaging agent precursors useful inthe preparation of imaging agents as described herein are provided. Incertain embodiments, an imaging agent precursor as described hereincomprises a leaving group (e.g., a sulfonate, halide) that can bereplaced with a nucleophile in a substitution reaction. The imagingagent precursor may also include functional groups that are optionallyprotected. Earlier precursors in the synthesis of imaging agents asdescribed herein are also encompassed by the present invention. In someembodiments, an imaging agent precursor has a structure as describedabove for a compound of Formula (Ia)-(Id), (IIa)-(IIb), (III), (IV),(Va)-(Vd), (VI), or (VII), except that the substituent which includesthe imaging moiety instead includes a leaving group or a chelator groupwhich is not yet associated with an imaging moiety.

In certain embodiments, a compound (e.g., an imaging agent precursor)for preparing an imaging agent is provided comprising Formula (VIII):

R^(0′)—Ar-L-R¹  (VIII)

wherein

Ar is substituted or unsubstituted, monocyclic or bicyclic aryl orsubstituted or unsubstituted, monocyclic or bicyclic heteroaryl;

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R^(0′) is halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A2))₂,—N(R^(A2))₃ ⁺, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —OSO₂R^(A1), —Si(R^(A1))₃,—Sn(R^(A1))₃, —B(OR^(A1))₂, —NR^(A2)SO₂R^(A1), —NO₂, —SO₂N(R^(A2))₂,—CN, —SCN, or —NO₂; or R^(0′) is substituted with a leaving group or isa leaving group; and

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; or a salt thereof. In some embodiments, a compound of Formula(VIII) is not of the formula:

wherein L_(G) is a leaving group.

In some embodiments, Ar, L, and/or R¹ may be as described herein, forexample, as described for a compound of Formula (Ia).

As used herein, the term “leaving group” is given its ordinary meaningin the art of synthetic organic chemistry and refers to an atom or agroup capable of being displaced by a nucleophile. Examples of suitableleaving groups include, but are not limited to, halides (such aschloride, bromide, or iodide), alkoxycarbonyloxy, aryloxycarbonyloxy,alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy),arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, andhaloformates. In some cases, the leaving group is a sulfonic acid ester,such as toluenesulfonate (tosylate, Ts), methanesulfonate (mesylate,Ms), p-bromobenzenesulfonyl (brosylate, Bs), ortrifluoromethanesulfonate (triflate, Tf). In some cases, the leavinggroup is a brosylate, such as p-bromobenzenesulfonyl. In some cases, theleaving group is a nosylate, such as 2-nitrobenzenesulfonyl. In someembodiments, the leaving group is a sulfonate-containing group. In someembodiments, the leaving group is a tosylate group. The leaving groupmay also be a phosphineoxide (e.g., formed during a Mitsunobu reaction)or an internal leaving group such as an epoxide or cyclic sulfate.

In some embodiments, the leaving group is a sulfonate leaving group. Insome embodiments, R^(0′) is selected from the group consisting of alkoxysubstituted with a leaving group, alkyl substituted with a leavinggroup, and R^(0′) is alkoxyalkyl (e.g., alkoxymethyl) substituted with aleaving group. In some embodiments, R^(0′) is —OCH₂L_(G), —OCH₂CH₂L_(G),—OCH₂CH₂CH₂L_(G), or OCH₂CH₂CH₂CH₂L_(G). In certain embodiments, R^(0′)is —CH₂L_(G), —CH₂CH₂L_(G), —CH₂CH₂CH₂L_(G), or —CH₂CH₂CH₂CH₂L_(G). Incertain embodiments, R^(0′) is —CH₂OCH₂L_(G), —CH₂OCH₂CH₂L_(G),—CH₂OCH₂CH₂CH₂L_(G), or —CH₂OCH₂CH₂CH₂CH₂L_(G). In certain embodiments,R^(0′) is:

wherein n is an integer between 0 and 6, inclusive; m is an integerbetween 0 and 6, inclusive; and R⁷ is substituted or unsubstituted,cyclic or acyclic alkyl; substituted or unsubstituted, cyclic or acyclicalkenyl; substituted or unsubstituted, cyclic or acyclic alkenyl;substituted or unsubstituted, cyclic or acyclic heteroaliphatic;substituted or unsubstituted aryl; substituted or unsubstitutedheteroaryl, substituted or unsubstituted arylalkyl; or substituted orunsubstituted heteroarylalkyl.

In some embodiments, R^(0′) is alkoxy substituted with a leaving group.In some embodiments, R^(0′) is —OCH₂L_(G), —OCH₂CH₂L_(G),—OCH₂CH₂CH₂L_(G), or —OCH₂CH₂CH₂CH₂L_(G).

In some embodiments, R^(0′) is alkyl substituted with a leaving group.In some embodiments, R^(0′) is —CH₂L_(G), —CH₂CH₂L_(G), —CH₂CH₂CH₂L_(G),or —CH₂CH₂CH₂CH₂L_(G).

In some embodiments, R^(0′) is alkoxyalkyl substituted with a leavinggroup. In some embodiments, R^(0′) is of the formula:

wherein n is an integer between 0 and 6, inclusive; m is an integerbetween 0 and 6, inclusive; and R⁷ is substituted or unsubstituted,cyclic or acyclic alkyl; substituted or unsubstituted, cyclic or acyclicalkenyl; substituted or unsubstituted, cyclic or acyclic alkenyl;substituted or unsubstituted, cyclic or acyclic heteroaliphatic;substituted or unsubstituted aryl; substituted or unsubstitutedheteroaryl, substituted or unsubstituted arylalkyl; or substituted orunsubstituted heteroarylalkyl. In some embodiments, R⁷ is substituted orunsubstituted C₁-C₆ alkyl. In some embodiments, R⁷ is methyl. In someembodiments, R⁷ is —CF₃. In some embodiments, R⁷ is substituted orunsubstituted aryl. In some embodiments, R⁷ is substituted orunsubstituted phenyl. In some embodiments, R⁷ is:

In some embodiments, R^(0′) is alkoxymethyl substituted with a leavinggroup. In some embodiments, R^(0′) is —CH₂OCH₂L_(G), —CH₂OCH₂CH₂L_(G),—CH₂OCH₂CH₂CH₂L_(G), or —CH₂OCH₂CH₂CH₂CH₂L_(G).

In certain embodiments, a compound (e.g., an imaging agent precursor)for preparing an imaging agent is provided comprising Formula (IX):

R⁰—Ar-L-R^(1′)  (IX)

wherein

Ar is substituted or unsubstituted, monocyclic or bicyclic aryl orsubstituted or unsubstituted, monocyclic or bicyclic heteroaryl;

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R⁰ is halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A2))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂,—NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1),—NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1),—C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1),—OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂; and

R^(1′) is a substituted or unsubstituted nitrogen-containing moiety, andR^(1′) substituted with a leaving group;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; or a salt thereof.

In some embodiments, Ar, L, and/or R⁰ for a compound of Formula (IX) isas described for a compound of Formula (Ia).

In some embodiments, for a compound of Formula (IX), R¹ is —N(R^(A))₂,heteroaryl, heterocyclic, —C(═NH)NH₂, —NHC(═NH)NH₂,—NR^(A)C(═NR^(A))N(R^(A))₂; —NHC(═NH)NHR^(A), or —NHC(═NH)N(R^(A))₂,wherein each occurrence of R^(A) is independently hydrogen, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl, or two R^(A) groups may be joined to form an optionalsubstituted heterocyclic ring, provided R^(1′) comprises at least oneleaving group. In some embodiments, R¹ is a non-aromatic, cyclic,substituted or unsubstituted nitrogen-containing moiety comprising atleast one leaving group. In some embodiments, R¹ is selected from thegroup consisting of —NHC(═NH)NH₂, —NH₂, —NHR^(A) (wherein R^(A) is asdefined herein), —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃,

each substituted with at least one leaving group, and optionally othersubstituents.

In certain embodiments, a compound is provided comprising Formula (X):

wherein

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

each of R²-R⁶ is independently hydrogen, halogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,—OR^(A1), —N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1),—C(═O)SR^(A1), —C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1),—OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2),—NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂,—SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂,—C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A)1, —C(═NR^(A2))SR^(A1),—C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A)1, —OC(═NR^(A2))OR^(A)1,—OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂; orany two adjacent R²-R⁶ are joined to form an optionally substituted orunsubstituted carbocyclic, heterocyclic, aryl, or heteroaryl ring; and

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; and

wherein at least one of R¹-R⁶ is substituted with a leaving group.

For example, in some embodiments for a compound of Formula (X), R⁴ canbe substituted with a leaving group, and is represented as R^(4′),wherein R^(4′) is selected from the group consisting of hydrogen,halogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, —OR^(A1), —N(R^(A2))₂, —SR^(A1),—C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂,—NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1),—NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1),—C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1),—OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂, eachsubstituted with a leaving group. In some cases, R^(4′) is selected fromthe group consisting of C₁₋₆alkyl, alkoxy, or alkoxyalkyl, eachsubstituted with a leaving group. In some cases, R^(4′) is alkoxymethylsubstituted with a leaving group. In some cases, R^(4′) is selected fromthe group consisting of —CH₂L_(G), —CH₂CH₂L_(G), —CH₂CH₂CH₂L_(G),—CH₂CH₂CH₂CH₂L_(G), —OCH₂L_(G), —OCH₂CH₂L_(G), —OCH₂CH₂CH₂L_(G),—OCH₂CH₂CH₂CH₂L_(G), —CH₂OCH₂L_(G), —CH₂OCH₂CH₂L_(G),—CH₂OCH₂CH₂CH₂L_(G), or —CH₂OCH₂CH₂CH₂CH₂L_(G), wherein L_(G) is aleaving group.

In some embodiments, R^(4′) is alkyl substituted with a leaving group.In some embodiments, R⁴ is C₁₋₆alkyl substituted with a leaving group.In some embodiments, R⁴ is —CH₂L_(G), —CH₂CH₂L_(G), —CH₂CH₂CH₂L_(G), or—CH₂CH₂CH₂CHL_(G). In some embodiments, R⁴ is alkoxy substituted with aleaving group. In some embodiments, R^(4′) is —OCH₂L_(G), —OCH₂CH₂L_(G),—OCH₂CH₂CH₂L_(G), or —OCH₂CH₂CH₂CH₂L_(G).

In some embodiments, R^(4′) is alkoxyalkyl substituted with a leavinggroup. In some embodiments, R^(4′) is of the formula:

wherein n is an integer between 0 and 6, inclusive; and m is an integerbetween 0 and 6, inclusive. In some embodiments, R^(4′) is alkoxymethylsubstituted with a leaving group. In some embodiments, R⁴ is—CH₂OCH₂L_(G), —CH₂OCH₂CH₂L_(G), —CH₂OCH₂CH₂CH₂L_(G), or—CH₂OCH₂CH₂CH₂CH₂L_(G).

In some embodiments, the leaving group is a sulfonate leaving group. Insome embodiments, R^(4′) is

wherein n is an integer between 0 and 6, inclusive; m is an integerbetween 0 and 6, inclusive; and R⁷ is substituted or unsubstituted,cyclic or acyclic alkyl; substituted or unsubstituted, cyclic or acyclicalkenyl; substituted or unsubstituted, cyclic or acyclic alkenyl;substituted or unsubstituted, cyclic or acyclic heteroaliphatic;substituted or unsubstituted aryl; substituted or unsubstitutedheteroaryl, substituted or unsubstituted arylalkyl; or substituted orunsubstituted heteroarylalkyl. In some embodiments, R⁷ is substituted orunsubstituted C₁-C₆ alkyl. In some embodiments, R⁷ is methyl. In someembodiments, R⁷ is —CF₃. In some embodiments, R⁷ is substituted orunsubstituted aryl. In some embodiments, R⁷ is substituted orunsubstituted phenyl. In some embodiments, R⁷ is:

Furthermore, each of the R^(4′) groups described herein in connectionwith a compound of Formula (X) may be combined with any suitable R¹and/or L group described above, for example, in connection with acompound of Formula (Ia).

In some embodiments, R³ is substituted with a leaving group, and cantherein be represented as R^(3′), wherein R^(3′) may be any R^(4′) groupas described herein in connection with a compound of Formula (IX).

In some embodiments, a compound of Formula (X) comprises Formula (XI):

wherein

L is a bond; substituted or unsubstituted alkylene; substituted orunsubstituted alkenylene; or substituted or unsubstitutedheteroalkylene;

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

R³ is hydrogen, halogen, optionally substituted alkyl, —OR^(A1),—N(R^(A2))₂, —C(═O)R^(A1), —C(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A1), or—CN;

R⁴ is hydrogen, halogen, optionally substituted alkyl, —OR^(A1),—N(R^(A2))₂, —C(═O)R^(A1), —C(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A1), or—CN;

each occurrence of R^(A1) is independently hydrogen, or optionallysubstituted alkyl; and each occurrence of R^(A2) is independentlyhydrogen or optionally substituted alkyl, or two R^(A2) groups arejoined to form an optionally substituted heterocyclic ring; and

wherein at least one of R³ and R⁴ is substituted with an leaving group;or a salt thereof.

The compound of Formula (XI) may comprise any suitable R³ and/or R⁴group(s) as described herein in connection with a compound of Formula(X), provided at least one of R³ and R⁴ is substituted with a leavinggroup (i.e., thereby being R^(3′) or R^(4′)), and/or any L and/or R¹group as described herein, for example, in connection with a compound ofFormula (Ia).

In some embodiments, a compound of Formula (XI) comprises the structure:

or salt thereof, wherein R^(4′) and R^(3′) may be any suitable R^(4′)and R^(3′) as described herein in connection with a compound of Formula(X) (e.g., is substituted with a leaving group). In some embodiments, acompound of Formula (XI) comprises the structure:

R¹ may be any suitable R¹ as described in connection with a compound ofFormula (Ia); R^(3′) and R^(4′) may be any suitable R^(3′) and R^(4′) asdescribed herein in connection with a compound of Formula (X). In someembodiments, a compound of Formula (X) comprises the structure:

R¹ may be any suitable R¹ as described in connection with a compound ofFormula (Ia); R^(3′) and R^(4′) may be any suitable R^(3′) and R^(4′) asdescribed above in connection with a compound of Formula (X).

In some embodiments a compound of Formula (X) comprises Formula (XII):

wherein

L is a bond; substituted or unsubstituted alkylene; substituted orunsubstituted alkenylene; or substituted or unsubstitutedheteroalkylene;

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

R³ is halogen, optionally substituted alkyl, —OR^(A1), —N(R^(A2))₂,—C(═O)R^(A1), —C(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A1), or —CN;

R⁴ is hydrogen, halogen, optionally substituted alkyl, —OR^(A1),—N(R^(A2))₂, —C(═O)R^(A1), —C(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A1), or—CN;

R⁵ is halogen, optionally substituted alkyl, —OR^(A1), —N(R^(A2))₂,—C(═O)R^(A1), —C(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A1), or —CN;

each occurrence of R^(A1) is independently hydrogen, or optionallysubstituted alkyl; and each occurrence of R^(A2) is independentlyhydrogen or optionally substituted alkyl, or two R^(A2) groups arejoined to form an optionally substituted heterocyclic ring; and

one or more of R³ and R⁴ is substituted with a leaving group; or a saltthereof.

The compound of Formula (XII) may comprise any suitable R³ and/or R⁴ asdescribed herein, for example, in connection with a compound of Formula(X), provided at least one of R³ or R⁴ is substituted with a leavinggroup (i.e., thereby being R^(3′) or R^(4′)). For a compound of Formula(XII), any suitable combination of R¹, R⁵, and L groups may be used asdescribed herein. For example, wherein R¹ is as described in connectionwith a compound of Formula (IV) or (Ia), and/or L is as described inconnection with a compound of Formula (Ia).

In some embodiments, compound is provided comprising Formula(XIIIa)-(XIIId):

wherein

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

R² is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

R³ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

each occurrence of R⁴ is independently hydrogen, halogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —OR^(A1), —N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1),—C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂, —OC(═O)R^(A1),—OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2),—NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂,—SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂,—C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1),—C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1),—OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring;

provided at least one R⁴ is substituted with a leaving group; or a saltthereof.

For a compound of Formula (XIIIa)-(XIIId), any suitable combination ofR¹, R², R³, R⁴, and L groups may be used as described herein, providedat least one R⁴ group is substituted with a leaving group (e.g., andthus is R^(4′)).

In some cases, a compound of Formula (XIIIa)-(XIIId) comprises thestructure:

wherein R¹, R², R³, R⁴, and L are as described herein, provided at leastone R⁴ is R^(4′). For example, wherein R¹ is as described in connectionwith a compound of Formula (IV) or (Ia)-(Id), R³ and/or R⁴ is asdescribed in connection with a compound of Formula (IIa) or (IV), and/orL is as described in connection with a compound of Formula (Ia),provided at least one R⁴ is substituted with a leaving group (and thusis R^(4′)). In some cases, compound of Formula (XIIIa)-(XIIId) comprisesthe structure:

In some cases, a compound of Formula (XIIIa)-(XIIId) comprises thestructure:

In some cases a compound of Formula (XIIIa)-(XIIId) comprises thestructure:

In some cases, a compound of Formula (XIIIa)-(XIIId) comprises thestructure:

In some cases, a compound of Formula (XIIIa)-(XIIId) comprises thestructure:

In some cases, a compound of Formula (XIIIa)-(XIIId) comprises thestructure:

In some cases, a compound of Formula (XIIIa)-(XIIId) comprises thestructure:

In some cases, a compound of Formula (XIIIa)-(XIIId) comprises thestructure:

In some cases, a compound of Formula (XIIIa)-(XIIId) comprises thestructure:

In some cases, a compound of Formula (XIIIa)-(XIIId) comprises thestructure:

In some embodiments, a compound is provided comprising Formula (XIV):

wherein

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

R² is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

R³ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

R⁴ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

provided at least one R⁴ is substituted with a leaving group;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; or a salt thereof.

For a compound of Formula (XIV), any suitable combination of R¹, R², R³,R⁴, and L groups may be used as described herein, provided at least oneR⁴ is substituted with a leaving group, so that it is R^(4′). Forexample, wherein R¹ is as described in connection with a compound ofFormula (IV) or (Ia), R³ and/or R⁴ is as described in connection with acompound of Formula (IIa) or (IV), and/or L is as described inconnection with a compound of Formula (Ia), provided at least one R⁴ issubstituted with a leaving group.

In some embodiments, a compound of Formula (XIV) comprises thestructure:

wherein R¹, R^(4′), and L are as described herein. For example, whereinR¹ is as described in connection with a compound of Formula (IV) or(Ia), R^(4′) is as described in connection with a compound of Formula(VIII), and/or L is as described in connection with a compound ofFormula (Ia). In some embodiments, a compound of Formula (XIV) comprisesthe structure:

In some embodiments, imaging agent precursor comprises Formula (XV):

wherein

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

R² is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

R³ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

R⁴ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1),—N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),—C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1),—NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1),—C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂,—OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1),—OC(═NR^(A2))N(R^(A2))₂, —NR^(A2)C(═NR^(A2))R^(A2),—NR^(A2)C(═NR^(A2))OR^(A1), —NR^(A2)C(═NR^(A2))SR^(A1),—NR^(A2)C(═NR^(A2))N(R^(A2))₂, —SC(═NR^(A2))R^(A1),—SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1), —SC(═NR^(A2))N(R^(A2))₂,—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A2))₂,—OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1), —OC(═S)N(R^(A2))₂,—NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1), —NR^(A2)C(═S)SR^(A1),—NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A2))₂, —S(═O)R^(A1), —SO₂R^(A1), —NR^(A2)SO₂R^(A1),—SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

provided at least one R⁴ is substituted with a leaving group;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; or a salt thereof.

For a compound of Formula (XV), any suitable combination of R¹, R², R³,R⁴, and L groups may be used as described herein provided at least oneR⁴ is substituted with a leaving group (and thus is R^(4′)). Forexample, wherein R¹ is as described in connection with a compound ofFormula (IV) or (Ia), R³ and/or R⁴ is as described in connection with acompound of Formula (IIa) or (IV), and/or L is as described inconnection with a compound of Formula (Ia), provided at least one R⁴ issubstituted with a leaving group (and thus is R^(4′)).

In some embodiments, a compound of Formula (XV) comprises the structure:

wherein R¹, R^(4′), and L are as described herein.

D. Salts

As described herein, the imaging agents and precursors described hereinmay be salts. In some cases, the salt may be a pharmaceuticallyacceptable salt. Those of ordinary skill in the art will be aware ofsuitable counter anions for forming a salt of the imaging agents andimaging agent precursors described herein. In addition, those ofordinary skill in the art will be aware that the counter anion X θ mayhave a charge of greater than (−1) (e.g., (−2), (−3)), and in suchembodiments, each counter anion X θ may be associated with more than onemolecule of a compound. In some embodiments, the counter ion is halide,phosphate, hydrogen phosphate, dihydrogen phosphate, hydrogen sulfate,sulfate, trifluoroacetate, toluenesulfonate, acetate, formate, citrate,ascorbate, mesylate (methanesulfonate), triflate(trifluoromethanesulfonate), tartrate, lactate, or benzoate. Additionalnon-limiting examples of suitable counter anions include the conjugatebase of inorganic acids (e.g., chloride, bromide, iodide, fluoride,nitrate, sulfate, phosphate) or from the conjugate base of organic acids(e.g., carboxylate, acetate, benzoate, tartrate, adipate, lactate,formate, maleate, glutamate, ascorbate, citrate, gluconate, oxalate,succinate, pamoate, salicylate, isethionate, succinamate,mono-diglycollate, di-isobutyrate, glucoheptonate). Still yet othernon-limiting examples of salts include adipate, alginate,aminosalicylate, anhydromethylenecitrate, arecoline, aspartate,bisulfate, camphorate, digluconate, dihydrobromide, disuccinate,glycerophosphate, hemisulfate, fluoride, iodide,methylenebis(salicylate), napadisylate, oxalate, pectinate, persulfate,phenylethylbarbiturate, picrate, propionate, thiocyanate, tosylate,undecanoate, acetate, benzenesulfonate, benzoate, bicarbonate,bitartrate, bromide, calcium edentate, camyslate, carbonate, chloride,citrate, dihydrochloride, edentate, edisylate, estolate, esylate,fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,hexylresorcinate, hydrabamine, bromide, chloride, hydroxynaphthoate,iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate,mesylate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate,subacetate, succinate, sulfate, tannate, tartrate, teoclate, andtriethiodide (see Berge et al., Journal of Pharmaceutical Sciences,66(1), 1977, 1-19).

E. Methods of Synthesizing an Imaging Agent

In other aspects, methods are provided for synthesizing imaging agents.The methods described herein may be used for the synthesis of a varietyof imaging agents as described herein from imaging agent precursors asdescribed herein. Generally, an imaging agent may be synthesized byreacting an imaging agent precursor with a reactant comprising theimaging moiety. In some cases, the reaction involves the formation of acovalent bond between the imaging agent precursor and the imaging moietyof the reactant. In other cases, however, the reaction involvesnon-covalent association of an imaging moiety with an imaging agentprecursor (e.g., via chelation). The following sections provide a numberof non-limiting embodiments for forming an imaging agent from an imagingagent precursor. Those of ordinary skill in the art will be aware ofother suitable methods and techniques for forming an imaging agent froman imaging agent precursor. In addition, other steps which may beconducted in connection with the synthesis of an imaging agent (e.g.,formulation, purification) are also described.

E1. General Reaction Conditions

The synthetic methods described herein may be carried out in anysuitable solvent, including, but are not limited to, non-halogenatedhydrocarbon solvents (e.g., pentane, hexane, heptane, cyclohexane),halogenated hydrocarbon solvents (e.g., dichloromethane, chloroform,fluorobenzene, trifluoromethylbenzene), aromatic hydrocarbon solvents(e.g., toluene, benzene, xylene), ester solvents (e.g., ethyl acetate),ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether,dimethoxyethane), and alcohol solvents (e.g., ethanol, methanol,propanol, isopropanol, tert-butanol). In certain embodiments, a proticsolvent is used. In other embodiments, an aprotic solvent is used.Non-limiting examples of solvents useful include acetone, acetic acid,formic acid, dimethyl sulfoxide, dimethyl formamide, acetonitrile,p-cresol, glycol, petroleum ether, carbon tetrachloride,hexamethyl-phosphoric triamide, triethylamine, picoline, and pyridine.

The methods may be carried out at any suitable temperature. In somecases, the method is carried out at about room temperature (e.g., about20° C., between about 20° C. and about 25° C., about 25° C., or thelike). In some cases, however, the method is carried out at atemperature below or above room temperature, for example, at about −78°C. at about −70° C., about −50° C., about −30° C., about −10° C., about−0° C., about 10° C., about 30° C., about 40° C., about 50° C., about60° C., about 70° C., about 80° C., about 90° C., about 100° C., about120° C., about 140° C., or the like. In some embodiments, the method iscarried out at temperatures above room temperature, for example, betweenabout 25° C. and about 120° C., or between about 25° C. and about 100°C., or between about 40° C. and about 120° C., or between about 80° C.and about 120° C. The temperature may be maintained by reflux of thesolution. In some cases, the method is carried out at temperaturesbetween about −78° C. and about 25° C., or between about 0° C. and about25° C.

The methods described herein may be carried out at any suitable pH, forexample, equal to or less than about 13, equal to or less than about 12,equal to or less than about 11, equal to or less than about 10, equal toor less than about 9, equal to or less than about 8, equal to or lessthan about 7, or equal to or less than about 6. In some cases, the pHmay be greater than or equal to 1, greater than or equal to 2, greaterthan or equal to 3, greater than or equal to 4, greater than or equal to5, greater than or equal to 6, greater than or equal to 7, or greaterthan or equal to 8. In some cases, the pH may be between about 2 andabout 12, or between about 3 and about 11, or between about 4 and about10, or between about 5 and about 9, or between about 6 and about 8, orabout 7.

The percent yield of a product may be greater than about 60%, greaterthan about 70%, greater than about 75%, greater than about 80%, greaterthan about 85%, greater than about 90%, greater than about 92%, greaterthan about 95%, greater than about 96%, greater than about 97%, greaterthan about 98%, greater than about 99%, or greater.

E2. Halogenation

In some embodiments, an imaging agent is formed by reacting an imagingagent precursor with an imaging moiety. In certain embodiments, animaging agent precursor comprises at least one leaving group that issusceptible to being displaced by an imaging moiety, such as, forexample, a halogen (e.g., ¹⁸F, ⁷⁶Br, ¹²⁴I, ¹³¹I). Thus, in certainembodiments, the methods described herein involve reacting an imagingagent precursor comprising a leaving group with a source of an imagingmoiety.

In some embodiments, an imaging moiety displaces a leaving group on aprovided imaging agent precursor via a substitution reaction, such as anS_(N)2 or S_(N)1 reaction, thereby producing an imaging agent. Incertain embodiments, a substitution reaction is a one-step procedurewhich does not require a subsequent deprotection step. That is, thesubstitution step is performed on a fully deprotected imaging agentprecursor. In certain embodiments, a substitution reaction provided bythe present invention produces a fluorinated imaging agent (e.g., animaging agent comprising ¹⁸F).

In some embodiments, a provided imaging agent is synthesized via an arylhalogenation reaction (e.g., aryl fluorination, aryl bromination, aryliodination). Many techniques for synthesizing aryl halides are known inthe art. For example, in certain embodiments, an imaging agentcomprising an ¹²⁴I, ¹³¹I, or ⁷⁶Br imaging moiety is synthesized via aSandmeyer reaction from a aryl diazonium imaging agent precursor, withor without the use of copper(I) catalysis (see, for example, Beletskayaet al., Synthesis, 2007, 2534-2538; Hubbard et al., J. Org. Chem., 2008,73, 316-319; Filimonov et al., Org. Lett., 2008, 10, 3961-3964;Krasnokutskaya et al., Synthesis, 2007, 81-84). In other embodiments, animaging agent comprising a ¹⁸F imaging moiety is synthesized via arelated Balz-Schiemann reaction from a diazonium imaging agentprecursor. In certain embodiments, an imaging agent comprising an ¹²⁴Ior ¹³¹I imaging moiety is synthesized via an “aromatic Finkelstein”reaction from an aryl bromide imaging agent precursor (see, for example,A. Klapars, S. L. Buchwald, J. Am. Chem. Soc., 2002, 124, 14844-14845).In other embodiments, an imaging agent comprising an ¹²⁴I, ¹³¹I, or ⁷⁶Brimaging moiety is synthesized by allowing a boronic acid or esterimaging agent precursor to react with the appropriate N-halosuccinimidereagent (Thiebes et al., Synlett, 1998, 141-142) or copper bromidereagent (see, for example, Murphy et al., J. Am. Chem. Soc., 2007, 129,15434-15435; Thompson et al., Synthesis, 2005, 547-550). In someembodiments, an imaging agent comprising a ⁷⁶Br imaging moiety issynthesized via an organotrifluoroborate imaging agent precursor (see,for example, G. W. Kabalka, A. R. Mereddy, Organometallics, 2004, 23,4519-4521). One of ordinary skill in the art will appreciate that thereare many other conditions under which activated or deactivated arenesmay be halogenated (see, for example, Kraszkiewicz et al., Synthesis,2006, 1195-1199; Ganguly et al., Synthesis, 2010, 1467-1472; Iskra etal., Synthesis, 2004, 1869-1873; Castanet et al., Tetrahedron Lett.,2002, 43, 5047-5048; Prakash et al., J. Am. Chem. Soc., 2004, 126,15570-15776; Lulinski et al., Synthesis, 2004, 441-445; Ganguly et al.,Synthesis, 2005, 1103-1108; Rajesh et al., Org. Chem., 2007, 72,5867-5869; Kumar et al., Synthesis, 2010, 1629-1632; Zhou et al.,Synthesis, 2011, 207-209; Menzel et al., J. Org. Chem., 2006, 71,2188-2191), and such a reaction may be employed in certain embodimentsto synthesize imaging agents described herein. One of ordinary skill inthe art will also appreciate that many of the aryl halogenationreactions described herein will also be effective for generating ahaloalkene- or haloalkyne-containing imaging agent, as well ashaloheteroaryl-containing imaging agents.

In some embodiments, an imaging agent comprising a ¹⁸F imaging moiety issynthesized via an aryl fluorination. See, for example, Furuya et al.,Synthesis, 2010(11): 1804-1821 (2010), for an informative review of arylfluorination reactions. For example, in certain embodiments, an imagingagent comprising a ¹⁸F imaging moiety is synthesized via an nucleophilicfluorination reaction. Examples of nucleophilic fluorination reactionsinclude, but are not limited to, the Halex process (Adams et al., ChemSoc Rev 1999; 28:225; Horwitz et al., J. Org. Chem 1961; 26:3392; Barlinet al., J. Chem. Soc., Perkin Trans 1 1972:1269; Pike et al., J. Chem.Soc., Chem Commun 1995:2215; Shah et al., J. Chem. Soc., Perkin Trans 11998:2043; Ermert et al., J Labelled Compd Radiopharm 2004; 47:429),fluorodenitration (Adams et al., Chem Soc Rev 1999; 28:225; Adams etal., J. Fluorine Chem 1998; 92:127), displacement of ammonium withfluoride (Angelini et al., J. Fluorine Chem 1985; 27:177), andfluorination of diaryliodonium salts (Zhdankin et al., Chem Rev 2008;108:5299; Beringer et al., J. Am. Chem Soc 1953; 75:2708; Ross et al.,J. Am. Chem Soc 2007; 129:8018). Trialkylammonium fluoride reagents mayalso be employed in nucleophilic fluorination reactions (Sun et al.,Angew. Chem., Int. Ed 2006; 45:2720; Grushin et al., Organometallics2008; 27:4825). In certain embodiments, a nucleophilic fluorinationreaction is Palladium catalyzed (see, for example, Grushin et al.,Organometallics 2008; 27:4825; Watson et al., Science 2009; 325:1661).In other embodiments, an imaging agent comprising a ¹⁸F imaging moietyis synthesized via an electrophilic fluorination reaction. Examples ofelectrophilic fluorination reactions include, but are not limited to,fluorination of aryl Grignards reagents (Anbarasan P, Neumann H, BellerM. Angew Chem, Int Ed. 2010; 49:2219), fluorination of arylmagnesiumreagents (Yamada S, Gavryushin A, Knochel P. Angew Chem, Int Ed. 2010;49:2215), fluorination of organometallic reagents such as arylzinchalides, arylsilanes, arylstannanes, arylgermaniums, or arylboronicacids (Bryce et al., J. Chem. Soc, Chem Commun 1986:1623; Tius et al.,Synth Commun 1992; 22:1461; Cazorla et al., Tetrahedron Lett 2009;50:3936), fluorination of arylsilanes (Lothian et al., Synlett1993:753), and fluorodestannylation reactions (Lothian et al., Synlett1993:753; Namavari et al., Appl Radiat Isot 1992; 43:989.). In someembodiments, an electrophilic fluorination reaction employsstoichiometric or catalytic palladium (see, for example, Furuya et al.,Angew Chem, Int Ed 2008; 47:5993) or silver (see, for example, Furuya etal., J. Am. Chem Soc 2009; 131:1662; Furuya et al., Org Lett 2009;11:2860).

In some embodiments, a method of synthesizing an imaging agent describedherein involves the use of one or more reagents (e.g., salts, catalysts)that facilitate a chemical reaction (e.g., a substitution reaction). Incertain embodiments, a choice of salt form allows for fluorination of anunprotected imaging agent precursor. Without wishing to be bound by aparticular theory, the counter anion may interact with the guanidinefunctional group or other nitrogen-containing group preventing it frominterfering with the fluorination reaction and/or preventing sidereactions. In certain embodiments, the salt is a mesylate (i.e.,methanesulfonate), phosphate, sulfate, acetate, formate, benzoate,trifluoroacetate, or tosylate salt.

In some embodiments, multiple substitution reactions may occur throughmultiple leaving groups during synthesis of an imaging agent from animaging agent precursor. The methods described herein exhibit improvedyields may allow for the synthesis of imaging agents, including imagingagents comprising a radioisotope (e.g., ¹⁸F). The imaging agents may beuseful as sensors, diagnostic tools, and the like. Synthetic methods forpreparing an imaging agent have also been designed to use an automatedsynthesis system to prepare and purify imaging agents that are enrichedwith a radioisotope.

E3. Fluorination

It should be understood, that while the following section focuses onfluorination reactions, this is by no means limiting, and the teachingof this section may be applied to other halogenation reactions.

In some embodiments, an imaging moiety displaces a leaving group on aprovided imaging agent precursor via a substitution reaction, such as anS_(N)2 or S_(N)1 reaction, thereby producing an imaging agent. Incertain embodiments, a substitution reaction is a one-step procedurewhich does not require a subsequent deprotection step. That is, thesubstitution step is performed on a fully deprotected imaging agentprecursor. In certain embodiments, a substitution reaction provided bythe present invention produces a fluorinated imaging agent (e.g., animaging agent comprising ¹⁸F).

In some embodiments, a method for synthesizing an imaging agentcomprises contacting an imaging agent precursor of the invention (e.g.,a compound of Formula (VIII)) with a fluoride species resulting in thefluoride species replacing the leaving group of the precursor to producean imaging agent (e.g., a compound of Formula (Ia)) comprising thefluorine species).

In some embodiments, an inventive method employs a reaction describedherein, such as in the description of halogenation reactions above. Forexample, in certain embodiments, a compound of Formula (VIII) istransformed to a compound of Formula (Ia) using a nucleophilicsubstitution reaction, an electrophilic substitution reaction, or anorganometallic reaction as described herein.

In certain embodiments, a method according to the invention involves anucleophilic fluorination reaction. It will be understood that thediscussion of nucleophilic fluorination is exemplary of the methodsdescribed herein and is not limiting. In certain embodiments, an imagingagent precursor comprising a leaving group is reacted in the presence ofa fluoride species, whereby S_(N)2 or S_(N)1 displacement of the leavinggroup by the fluoride species produces an imaging agent. In someembodiments, a fluoride species is isotopically enriched with ¹⁸F.

Those of ordinary skill in the art will be aware of suitable conditionsfor fluorinating a compound. For example, see International PatentApplication No. PCT/US2011/024109, filed Feb. 8, 2011, published asInternational Patent Publication No. WO/2011/097649, by Cesati et al.,incorporated herein by reference. In some cases, a compound of Formula(VIII), or a salt, free base, or combination thereof, is exposed to asource of fluorine, optionally enriched with an isotope of fluorine(e.g., enriched with ¹⁸F). In some cases, the source of fluorine is afluoride salt (e.g., KF, NaF, tetralkylammonium fluoride).

The following provides a specific non-limiting example of a method ofthe present invention, comprising reaction an imaging agent precursorwith a fluoride species to form an imaging agent. In desired, at least aportion of the imaging agent may optionally be deprotected (e.g., aguanidine functional group) and/or purified prior to use. In certainembodiments, the present invention provides a method comprising reactinga compound of Formula (VIII):

R^(0′)—Ar-L-R¹  (VIII)

wherein

Ar is substituted or unsubstituted, monocyclic or bicyclic aryl orsubstituted or unsubstituted, monocyclic or bicyclic heteroaryl;

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R^(0′) is halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A2))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂,—NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1),—NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1),—C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1),—OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂; andR⁰ is substituted with a leaving group L_(G) or is a leaving groupL_(G);

R¹ is a substituted or unsubstituted nitrogen-containing moiety;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; or a salt, free base, or combination thereof; with a fluorinatingreagent under suitable conditions to form a compound of Formula (Ia):

R⁰—Ar-L-R¹  (Ia)

R⁰ is halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A2))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂,—NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1),—NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1),—C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1),—OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂; andR⁰ is substituted with a fluorine.

As described herein, R^(0′) of formula (VIII) comprises a leaving group.In some embodiments, a leaving group according to the present inventionis a sulfonate leaving group. In some embodiments, R^(0′) is alkoxysubstituted with a leaving group. In certain embodiments, R^(0′) is—OCH₂L_(G), —OCH₂CH₂L_(G), —OCH₂CH₂CH₂L_(G), or —OCH₂CH₂CH₂CH₂L_(G). Insome embodiments, R^(0′) is alkyl substituted with a leaving group. Incertain embodiments, R^(0′) is —CH₂L_(G), —CH₂CH₂L_(G), —CH₂CH₂CH₂L_(G),or —CH₂CH₂CH₂CH₂L_(G). In some embodiments, R^(0′) is alkoxyalkylsubstituted with a leaving group.

In some embodiments, a method according to the present invention employsa compound of Formula (VIII) wherein R^(0′) is of the formula:

wherein n is an integer between 0 and 6, inclusive; m is an integerbetween 0 and 6, inclusive; and R⁷ is substituted or unsubstituted,cyclic or acyclic alkyl; substituted or unsubstituted, cyclic or acyclicalkenyl; substituted or unsubstituted, cyclic or acyclic alkenyl;substituted or unsubstituted, cyclic or acyclic heteroaliphatic;substituted or unsubstituted aryl; substituted or unsubstitutedheteroaryl, substituted or unsubstituted arylalkyl; or substituted orunsubstituted heteroarylalkyl.

In some embodiments, R⁷ is substituted or unsubstituted C₁-C₆ alkyl. Incertain embodiments, R⁷ is methyl. In certain other embodiments, R⁷ is—CF₃. In some embodiments, R₇ is substituted or unsubstituted aryl. Incertain embodiments, R⁷ is substituted or unsubstituted phenyl. Incertain embodiments, R⁷ is p-tolyl. In some embodiments, R^(0′) isalkoxymethyl substituted with a leaving group. In certain embodiments,R^(0′) is —CH₂OCH₂L_(G), —CH₂OCH₂CH₂L_(G), —CH₂OCH₂CH₂CH₂L_(G), or—CH₂OCH₂CH₂CH₂CH₂L_(G).

In some embodiments, a provided compound of Formula (VIII) for use insynthetic methods of the present invention is as described inembodiments herein. In some embodiments, a provided compound of Formula(Ia) for use in synthetic methods of the present invention is asdescribed in embodiments herein, such as a provided compound of Formula(Ib), (Ic), (Id), (IIa)-(IIb), (III), (IV), (Va)-(Vd), (VI), or (VII)and embodiments thereof described herein.

As described above, in certain embodiments, a compound of Formula (VIII)is allowed to react with a fluorinating reagent under suitableconditions to form a compound of Formula (Ia). In some embodiments, afluorinating agent for use in a provided method is a source of fluoride.In certain embodiments, a fluorinating agent for use in a providedmethod is NaF or KF. In certain embodiments, a fluorinating agent foruse in a provided method is isotopically enriched with ¹⁸F. In certainembodiments, suitable conditions for a fluorination reaction accordingto the present invention comprise the presence of an ammonium salt or abicarbonate salt.

The fluorine source may comprise or be associated with or may be used inconnection with another reagent. In some embodiments, an additionalreagent may be capable of enhancing the reactivity of the fluorinespecies or otherwise facilitating conversion of the precursor to theimaging agent. For example, in certain embodiments, an additionalreagent is used in combination with a multidentate ligand, such as acrown ether or a cryptand that is capable of chelating a metal ion. Incertain embodiments, a multidentate ligand is, for example,4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane (i.e.,Kryptofix® 222). In certain embodiments, when KF is a fluorine source,cryptands having a high affinity for potassium are useful as theychelate potassium and thereby increase the reactivity of the fluorideion. In some embodiments, cryptands having an affinity for potassiumnear that of Kryptofix® 222 (e.g., 75%, 80%, 85%, 90%, 95%, or more ofthe Kryptofix® 222's affinity for potassium) are used. The reactionconditions may comprise one or more solvents.

In some embodiments, the fluorination occurs in the presence of K₂CO₃and Kryptofix® 222 (or any another cryptand having affinity for thecation of interest, including for example potassium, near that ofKryptofix® 222) in MeCN (acetonitrile) alone or in combination witht-BuOH, as the solvent. In some embodiments, the molar ratio of K₂CO₃ toimaging agent precursor ranges from about 0.5:1 to about 5:1, forexample 0.5:1 to 1:1. In some embodiments, the molar ratio is about0.66:1.

In some embodiments, fluorination occurs in the presence oftetraalkylammonium carbonate or tetraalkylammonium bicarbonate in MeCNas the solvent. In some embodiments, the molar ratio oftetraalkylammonium carbonate or bicarbonate to imaging agent precursoris 5:1. In some embodiments, the molar ratio ranges from about 7:1 toabout 3:1, or from about 6:1 to about 4:1, or about 5.5:1 to about4.5:1. In some embodiments, the tetraalkylammonium cation may betetraethylammonium or tetrabutylammonium but it is not so limited.

In certain embodiments, the synthetic methods described herein involve asingle-step preparation of imaging agents of the invention (e.g.,compounds of Formula (Ia)-(Id), (IIa)-(IIb), (III), (IV), (Va)-(Vd),(VI), or (VII), or a salt, free base, or combination thereof). Incertain embodiments, a single-step method involves fluorination of acompletely or partially deprotected precursor in the presence of, forexample, K₂CO₃/Kryptofix® 222 (or other suitable alternatives toKryptofix® 222) or tetraalkylammonium carbonate or bicarbonate, in MeCNalone or in an MeCN mixture (such as an MeCN and t-BuOH mixture). Incertain embodiments, single-step preparation methods are particularlysuitable when particular salt forms of the imaging agent precursors ofthe invention are used, such as halide, acetate, formate, citric,ascorbate, trifluoroacetate, toluenesulfonate, benzoate, acetate,phosphate, sulfate, tosylate, and mesylate.

In some embodiments, an imaging agent precursor comprises a protectednitrogen functional group (e.g., a protected guanidine functional group)which may or may not be deprotected prior to, or in some instancesafter, fluorination. For example, a guanidine functional group may ormay not be deprotected prior to fluorination. In some embodiments, animaging agent precursor comprising a protected guanidine functionalgroup is fluorinated, optionally followed by deprotection. In otherembodiments, an imaging agent precursor comprising a protected guanidinefunctional group is deprotected (e.g., according to the methodsdescribed herein), followed by fluorination. As described herein, incertain embodiments, a fluorine source is isotopically enriched with¹⁸F.

In some embodiments, one or more reagents is used in a reaction mixturecomprising an imaging agent precursor and a fluoride species. A“reagent,” also referred to as an “additive,” is used herein to mean anychemical compound added to a reaction mixture. A reagent may be consumedor not consumed during the reaction. A reagent may be a stoichiometricor catalytic reagent. Exemplary reagents include catalysts, salts,oxidants, reductants, chelating agents, bases, acids, metals, phasetransfer reagents, and others as would be appreciated by one of skill inthe art.

A reagent may, in some embodiments, facilitate reaction between animaging agent precursor and a fluoride species and/or may aid instabilizing a resultant imaging agent. For example, in certainembodiments, a fluoride species may have relatively low reactivity(e.g., nucleophilicity), and addition of certain reagents may enhancethe reactivity of the fluoride species. As an illustrative embodiment, afluorine species may be a negatively charged fluoride ion (e.g., anisotopically enriched ¹⁸F ion), and a reagent may be used to bind to anypositively charged counter ions present within the reaction mixture,thereby enhancing the reactivity of the fluoride ion. An example of sucha reagent is a cryptand such as, but not limited to, Kryptofix (e.g.,Kryptofix®-222). In some embodiments, a reagent decreases the rate ofundesired side reactions, as described below.

In some embodiments, a reagent may be combined with a fluoride speciesprior to its contact with an imaging agent precursor. For example, incertain embodiments, a solution comprising a fluoride species and areagent is prepared, and the solution is added to an imaging agentprecursor. In other embodiments, a solid comprising a fluoride speciesand a reagent is prepared, and the solid is contacted with an imagingagent precursor in solution. In certain embodiments, a fluoride speciesis adsorbed onto a solid support (e.g., an anion exchange column), and asolution comprising the reagent is used to elute the fluoride speciesfrom the solid support. The eluted solution is then contacted with theimaging agent precursor, or is concentrated to produce a solid, which isthen contacted with the imaging agent precursor in solution.

In some embodiments, a provided reagent is a bicarbonate salt. As usedherein, the term “bicarbonate salt” refers to a salt comprising abicarbonate or hydrogen carbonate ion (HCO₃-ion). In some embodiments, abicarbonate salt is a metal bicarbonate, such as sodium bicarbonate,calcium bicarbonate, potassium bicarbonate, and magnesium bicarbonate.In certain embodiments, a bicarbonate salt is potassium bicarbonate(KHCO₃). In some embodiments, a bicarbonate salt comprises a non-metalcounter ion, such as ammonium bicarbonate. For example, a bicarbonatesalt may be a tetraalkylammonium bicarbonate salt having the formula,R₄NHCO₃, wherein R is alkyl. In some embodiments, R may be lower alkyl,such as methyl, ethyl, propyl, butyl, pentyl, hexyl, or the like. Incertain embodiments, the ammonium salt is Et₄NHCO₃. In otherembodiments, the salt is Me₄NHCO₃, i-Pr₄NHCO₃, n-Pr₄NHCO₃, n-Bu₄NHCO₃,i-Bu₄NHCO₃, or t-Bu₄NHCO₃.

In some embodiments, a provided reagent is a carbonate salt. As usedherein, the term “carbonate salt” refers to a salt comprising acarbonate ion (CO₃ ⁻² ion). In some embodiments, a carbonate salt is ametal carbonate, such as sodium carbonate, calcium carbonate, potassiumcarbonate, and magnesium carbonate. In certain embodiments, a carbonatesalt is potassium carbonate (K₂CO₃). In some embodiments, a carbonatesalt comprises a non-metal counter ion, such as ammonium carbonate. Forexample, a carbonate salt may be a tetraalkylammonium carbonate salthaving the formula, (R₄N)₂CO₃, wherein R is alkyl. In some embodiments,R may be a lower alkyl, such as methyl, ethyl, propyl, butyl, pentyl,hexyl, or the like. In certain embodiments, the ammonium salt is(Et₄N)₂CO₃. In other embodiments, the salt is (Me₄N)₂CO₃, (i-Pr₄N)₂CO₃,(n-Pr₄N)₂CO₃, (n-Bu₄N)₂CO₃, (i-Bu₄N)₂CO₃, or (t-Bu₄N)₂CO₃.

Without wishing to be bound by any particular theory, use ofbicarbonate, carbonate, and/or ammonium salts may aid in decreasing therate of competing reactions such as hydrolysis during nucleophilicfluorination of an imaging agent precursor.

In some embodiments, a reagent is a salt comprising a cation that formsa weakly coordinating salt with a fluoride species. As used herein, a“cation that forms a weakly coordinating salt with a fluoride species”refers to a cation that renders a fluoride species reactive in thecontext of a fluorination reaction. For example, a cation may notstrongly bind to the fluoride species, allowing the fluoride species toact as a nucleophile during a nucleophilic fluorination reaction. Thoseof ordinary skill the art would be able to select an appropriate cationthat would be suitable as a weakly coordinating counter ion for afluoride species. For example, a cation may be have a relatively largeatomic radius and/or may be a weak Lewis base. In some cases, a cationmay be selected to be lipophilic. In some cases, a cation may compriseone or more alkyl groups. Examples of weakly coordinating cationsinclude cesium ions, ammonium ions, weakly coordinating salts ofhexamethylpiperidindium, S(NMe₂)₃, P(NMe₂)₄, tetraalkylphosphoniumsalts, tetraarylphosphonium salts, (e.g. tetraphenylphosphonium),hexakis(dimethylamino)diphosphazenium, and tris(dimethylamino)sulfonium.

In some embodiments, a provided reagent is an ammonium salt, i.e., asalt comprising a substituted or unsubstituted ammonium ion. In someembodiments, an ammonium ion is a weakly coordinating cation. In someembodiments, an ammonium salt has the formula, R₄NX, where each R can bethe same or different and is alkyl, heteroalkyl, aryl, heteroaryl, orheterocyclic, each optionally substituted, and X is a negatively chargedcounter ion. In some cases, R is alkyl, heteroalkyl, aryl, heteroaryl,or heterocyclic, each optionally substituted. In some embodiments,ammonium salt may include a range of negatively charged counter ions,including halides, carbonates, and bicarbonates. Examples of ammoniumsalts include, but are not limited to, ammonium bicarbonate salts,ammonium hydroxide salts, ammonium acetate salts, ammonium lactatesalts, ammonium trifluoroacetate salts, ammonium methanesulfonate salts,ammonium p-toluenesulfonate salts, ammonium nitrate salts, ammoniumhalide salts (e.g., ammonium iodide salts), and ammonium bisulfatesalts.

In one set of embodiments, an ammonium salt is a tetraalkylammoniumsalt, such as a tetraalkylammonium bicarbonate salt. For example, anammonium salt may have the formula, R₄NHCO₃, wherein each R isindependently alkyl. In some cases, R is optionally substituted. In someembodiments, the alkyl group is a lower C₁-C₆ alkyl group. In someembodiments, an tetraalkylammonium salt is a basic tetraalkylammoniumsalt.

In some embodiments, a salt (e.g., bicarbonate salt and/or ammoniumsalt) may be utilized in the reaction such that the molar ratio of thesalt to the imaging agent precursor is less than or equal to about 10:1,or less than or equal to about 9:1, or less than or equal to about 8:1,or less than or equal to about 7:1 or less than or equal to about 6:1,or less than or equal to about 5:1, or less than or equal to about 4:1,or less than or equal to about 3:1, or less than or equal to about 2:1,or less than or equal to about 1:1. In some cases, the molar ratio ofthe salt to the imaging agent precursor is between about 3:1 and about8:1, or between about 4:1 and about 7:1, or between about 5:1 and about7:1, or between about 5:1 and about 8:1.

In some embodiments, a reagent is used in combination with a speciescapable of enhancing the reactivity of the fluoride species or otherwisefacilitating conversion of the imaging agent precursor to the imagingagent. For example, a species may be a compound capable of chelating oneor more ions (e.g., metal ions) that may be present within the reactionmixture. Without wishing to be bound by theory, a species may be used tochelate a counter ion to a fluoride species, such as a potassium ion,thereby increasing the reactivity (e.g., nucleophilicity) of thefluoride species. In certain embodiments, a reagent is used incombination with a multidentate ligand, such as a crown ether or acryptand that is capable of chelating a metal ion. The multidentateligand (e.g., cryptand) may be selected based on the metal ion to bechelated. A multidentate ligand may be, for example,4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane (e.g.,Kryptofix® 222). Other cryptands will be known to those of ordinaryskill in the art.

Some embodiments involve use of a carbonate salt in combination with4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane. In aspecific embodiment, potassium carbonate is used in combination with4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane.

In another set of embodiments, it may be advantageous to utilize themethods described herein in the absence of a cryptand. The term“cryptand” is given its ordinary meaning in the art and refers to a bi-or a polycyclic multidentate ligand for a cation. For example, inventivemethods may be carried out using an ammonium salt, in the absence of acryptand (e.g.,4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane). In someembodiments, cryptands may increase the pH of the reaction solution,which in the presence of another reagent (e.g. carbonate salt) mayadversely affect the yield and/or purity of the fluorination reaction.Accordingly, in certain embodiments, carrying out the fluorinationreaction, in the absence of a cryptand, and optionally in the presenceof another reagent (e.g., ammonium and/or bicarbonate salt) may increasethe yield and/or purity of the reaction, as described herein.

In another set of embodiments, a method according to the presentinvention is performed in the absence of a carbonate salt.

As will be understood by one of ordinary skill in the art, duringfluorination (or other halogenation reactions), any associated anionicspecies (e.g., in instances where the starting material is a salt) maybe exchanged. That is, in certain embodiments, the starting material maybe provided as a first salt (e.g., trifluoroacetate, chloride), and theisolated product (e.g., the fluorinated product) may be isolated as asecond, different salt (e.g., formate, ascorbate, citrate, ortrifluoroacetate). In some embodiments, following formation of a salt, acounter anion may be exchanged in an additional step. For example, anHCl salt of a compound may be exposed to a suitable reagent (e.g., AgOAcor AgOBz) such that the compound forms the corresponding salt of thereagent (e.g., acetate salt or benzoate salt, respectively). As anotherexample, a TFA salt of a compound may be exposed to a suitable reagent(e.g., phosphoric acid or methanesulfonic acid) such that the compoundforms the corresponding salt of the reagent (e.g., phosphate salt ormethanesulfonate salt, respectively). The intermediate salt (e.g.,trifluoroacetate salt or chloride salt in the above-examples) may or maynot be isolated prior to exposure to the reagent.

Those of ordinary skill in the art will be able to select and/ordetermine an appropriate set of reaction conditions (e.g.,concentration, temperature, pressure, reaction time, solvents) suitablefor use in a particular application. In some embodiments, an imagingagent may be further processed using one or more purificationtechniques, and may optionally be combined with additional components,such as a stabilizing agent.

In some embodiments, an imaging agent is formed as a salt (e.g., apharmaceutically acceptable salt). Pharmaceutically acceptableexcipients and other aspects of pharmaceutically acceptable compositionsare described herein.

Those of ordinary skill in the art would be able to select a source of afluoride species suitable for use in the methods described herein. Theterm “fluoride species” as used herein refers to a fluoride atom orgroup of atoms comprising at least one fluoride atom, wherein thefluoride atom is capable of reacting with another compound (e.g., animaging agent precursor). In some embodiments, an isotopically-enriched¹⁸F species may be produced by the nuclear reaction ¹⁸O(p,n)¹⁸F fromproton bombardment of [¹⁸O]H₂O in a cyclotron. In certain embodiments, amethod may involve treating a solution of the ¹⁸F species to remove anyimpurities, such as unreacted [¹⁸O]H₂O. For example, a solution of the¹⁸F species may be filtered through an anion exchange column, where the¹⁸F species is retained on the cationic resin matrix while the [¹⁸O]H₂Ois eluted. The ¹⁸F species is then removed by washing the anion exchangecolumn with various mixtures of solvents and optional reagents (e.g.,salt), forming an ¹⁸F-containing solution. In some embodiments, an anionexchange column is washed with an aqueous solution of a salt, such asK₂CO₃ or Et₄NHCO₃. In other embodiments, a column is washed (e.g., withaqueous K₂CO₃), and the resulting solution diluted (e.g., with MeCN)and/or concentrated (e.g., to dryness using elevated temperature and/orreduced pressure). Anhydrous [¹⁸F]KF and/or [¹⁸F]Et₄NF may be obtainedand reacted with a compound or a salt thereof.

In some embodiments, a ¹⁸F-containing solution is combined withadditional components prior to reaction with an imaging agent precursor.For example, one or more solvents may be added to dilute a¹⁸F-containing solution to a desired concentration. In certainembodiments, a ¹⁸F-containing solution is diluted with acetonitrile(MeCN). In certain embodiments, a ¹⁸F-containing solution is dilutedwith acetonitrile (MeCN) and t-BuOH.

In some embodiments, a ¹⁸F-containing solution may be concentrated todryness by exposure to elevated temperature and/or reduced pressure toform an anhydrous ¹⁸F-containing solid. In some embodiments, a¹⁸F-containing solid may further comprise one or more reagents (e.g.,salts). The chemical composition of a ¹⁸F-containing solid may depend onthe number and kind of reagents used in preparation of the¹⁸F-containing solution. For example, a solution of potassium carbonatemay be used to elute a ¹⁸F species from the anion exchange column,thereby resulting in an ¹⁸F-containing solid comprising [¹⁸F]KF. Inanother example, a solution of tetraethylammonium bicarbonate is used toelute a ¹⁸F species from the anion exchange column, thereby resulting inan ¹⁸F-containing solid comprising [¹⁸F]Et₄NF.

In some embodiments, a solution comprising a ¹⁸F species is heated to atemperature ranging from room temperature to about 200° C. For example,a solution comprising a [¹⁸F]-fluoride may be heated to elevatedtemperatures to encourage evaporation of the solvent (e.g., to about110° C.). In some embodiments, a solution is heated to a temperatureranging from about 90-120° C. or from about 100-150° C. In someembodiments, a solution is heated to about 75° C., about 85° C., about95° C., about 105° C., about 115° C., about 125° C., or greater. In someembodiments, a solution is placed under a reduced pressure of about 100mm Hg, about 125 mm Hg, about 150 mm Hg, about 175 mm Hg, about 200 mmHg, about 225 mm Hg, about 250 mm Hg, about 275 mm Hg, about 300 mm Hg,about 325 mm Hg, about 350 mm Hg, about 375 mm Hg, about 400 mm Hg, orgreater. In some embodiments, a solution is placed under a reducedpressure of about 100 mbar, about 125 mbar, about 150 mbar, about 175mbar, about 200 mbar, about 225 mbar, about 250 mbar, about 275 mbar,about 280 mbar, about 300 mbar, about 325 mbar, about 350 mbar, about375 mbar, about 400 mbar, about 450 mbar, about 500 mbar, or greater.Those of ordinary skill in the art would be able to select and/ordetermine conditions suitable for a particular process. In someembodiments, a solution is concentrated to dryness at about 150 mm Hgand about 115° C. In some embodiments, a solution is concentrated todryness at about 375 mm Hg and about 115° C. In some embodiments, asolution is concentrated to dryness at about 400 mbar and about 110-150°C. In some embodiments, a solution is concentrated to dryness at about280 mbar and about 95-115° C.

In certain embodiments, a fluoride species and/or a reagent, if present,is then contacted with an imaging agent precursor under conditions thatresult in conversion of the imaging agent precursor to the imaging agentproduct via nucleophilic fluorination. Those of ordinary skill in theart would be able to select conditions suitable for use in a particularreaction. For example, in certain embodiments, the ratio of fluoridespecies to imaging agent precursor may be selected to be about 1:10,000or more, about 1:5000 or more, about 1:3000 or more, about 1:2000 ormore, about 1:1000 or more, about 1:500 or more, about 1:100 or more,about 1:50 or more, about 1:10 or more, about 1:5 or more, or, in somecases, about 1:1 or more. In some embodiments, a fluoride species may bepresent at about 10 mol %, or about 5 mol %, or about 3 mol %, or about2 mol %, or about 1 mol % or about 0.5 mol %, or about 0.1 mol %, orabout 0.05 mol %, or about 0.01 mol % relative to the amount of imagingagent precursor. In some embodiments, a fluoride species is isotopicallyenriched with ¹⁸F. For example, in some embodiments, the ratio of ¹⁸Fspecies to imaging agent precursor may be selected to be about1:1,000,000 or more, or about 1:500,000 or more, or about 1:250,000 ormore, or about 1:100,000 or more, or about 1:50,000 or more, or about1:25,000 or more, or about 1:10,000 or more, about 1:5000 or more, about1:3000 or more, about 1:2000 or more, about 1:1000 or more, about 1:500or more, about 1:100 or more, about 1:50 or more, about 1:10 or more,about 1:5 or more, or, in some cases, about 1:1 or more.

In some embodiments, a nucleophilic fluorination reaction is carried outin the presence of one or more solvents, for example, an organicsolvent, a non-organic solvent (e.g., an aqueous solvent), or acombination thereof. In some embodiments, the solvent is a polar solventor a non-polar solvent. In some embodiments, the solvent is an aqueoussolution, such as water. In some embodiments, the solvent comprises atleast about 0.001% water, at least about 0.01% water, at least about0.1% water, at least about 1% water, at least about 5%, at least about10%, at least about 20% water, at least about 30% water, at least about40% water, at least about 50% water, or greater. In some embodiments,the solvent may comprise between about 0.1% and about 100% water, about1% to about 90%, about 1% to about 70%, about 1% to about 50%, or about10% to about 50%. In some embodiments, the solvent comprises no morethan about 10% water, about 5% water, about 4% water, about 3% water,about 2% water, about 1% water, or about 0.5% water. In someembodiments, the solvent comprises between about 0.01% water and about5% water, or between about 0.01% water and about 2% water, or betweenabout 0.1% water and about 0.2% water.

Other examples of solvents useful in the methods include, but are notlimited to, non-halogenated hydrocarbon solvents (e.g., pentane, hexane,heptane, cyclohexane), halogenated hydrocarbon solvents (e.g.,dichloromethane, chloroform, fluorobenzene, trifluoromethylbenzene),aromatic hydrocarbon solvents (e.g., toluene, benzene, xylene), estersolvents (e.g., ethyl acetate), ether solvents (e.g., tetrahydrofuran,dioxane, diethyl ether, dimethoxyethane), and alcohol solvents (e.g.,ethanol, methanol, propanol, isopropanol, tert-butanol). Othernon-limiting examples of solvents include acetone, acetic acid, formicacid, dimethyl sulfoxide, dimethyl formamide, acetonitrile, p-cresol,glycol, petroleum ether, carbon tetrachloride, hexamethyl-phosphorictriamide, triethylamine, picoline, and pyridine. In some embodiments, aprovided reaction is carried out in a polar solvent, such asacetonitrile. In some embodiments, a solvent may be selected so as toreduce and/or minimize the formation of side products. In certainembodiments, a fluorination reaction is carried out in MeCN as solvent.In certain embodiments, a fluorination reaction is carried out in t-BuOHas solvent. In certain embodiments, a fluorination reaction is carriedout in a mixture of MeCN and t-BuOH as solvent. In certain embodiments,a fluorination reaction is carried out in DMF as solvent. In certainembodiments, a fluorination reaction is carried out in DMSO as solvent.In certain embodiments, a fluorination reaction is carried out in THF assolvent.

In certain embodiments, an anhydrous ¹⁸F-containing solid, optionallycomprising a reagent, may be contacted with a solution of an imagingagent precursor (e.g., a tosylate precursor), and the resulting solutionis heated to an elevated temperature for a select period of time. Asolution may be, for example, an acetonitrile solution. In otherembodiments, a solution of an ¹⁸F species and reagent, if present, iscontacted with a solid imaging agent precursor or a solution of animaging agent precursor.

Some embodiments involve contacting an imaging agent precursor with afluoride species in a solution having a pH below about 13, below about12, or below about 11. In some cases, a solution has a pH between about8 and about 9, or between about 8 and about 10, or between about 7 andabout 8. In certain embodiments, a pH range for the fluorinationreaction is greater than about 6, or greater than about 7, or betweenand including 7-13, between and including 6-12, between and including7-12, between and including 8-12, between and including 9-12, andbetween and including 10-12.

In some cases, a solution comprising a ¹⁸F species, imaging agentprecursor, and, optionally, reagent, is heated to an elevatedtemperature for a period of time. For example, a solution may be heatedto about 50° C., about 60° C., about 70° C., about 80° C., about 90° C.,about 100° C., about 110° C., about 120° C., about 150° C., about 170°C., about 200° C., about 225° C., about 250° C., or greater, for aperiod of about 5 minutes or less, about 10 minutes or less, about 20minutes or less, about 30 minutes or less. It should be understood thatother temperatures and reaction times may be used. In some embodiments,upon completion of the reaction, the reaction mixture is cooled (e.g.,to room temperature) and optionally diluted with a solvent, such aswater, or mixtures of solvents, such as water/acetonitrile. In someembodiments, a reaction mixture is heated to elevated temperatures toencourage evaporation of the solvent (e.g., to about 95° C.). In someembodiments, a solution is heated to a temperature ranging from about55-125° C. In some cases, a solution is heated to about 65° C., about75° C., about 85° C., about 95° C., about 105° C., about 115° C., orgreater. In some cases, a solution is placed under a reduced pressure ofabout 100 mm Hg, about 125 mm Hg, about 150 mm Hg, about 175 mm Hg,about 200 mm Hg, about 225 mm Hg, about 250 mm Hg, about 275 mm Hg,about 300 mm Hg, about 325 mm Hg, about 350 mm Hg, about 375 mm Hg,about 400 mm Hg, or greater. In some cases, a solution is placed under areduced pressure of about 100 mbar, about 125 mbar, about 150 mbar,about 175 mbar, about 200 mbar, about 225 mbar, about 250 mbar, about275 mbar, about 280 mbar, about 300 mbar, about 325 mbar, about 350mbar, about 375 mbar, about 400 mbar, about 450 mbar, about 500 mbar, orgreater. Those of ordinary skill in the art would be able to selectand/or determine conditions suitable for a particular process. In someembodiments, a solution is concentrated to dryness under a flow of inertgas at about 95° C.

In some embodiments, upon completion of a fluorination reaction, theresulting imaging agent is optionally subjected to one or morepurification steps. In some embodiments, an imaging agent may bereconstituted in a solvent prior to purification (e.g., bychromatography such as HPLC). In some cases, an imaging agent isdissolved in water, acetonitrile, or combinations thereof. In someembodiments, following formation of a solution comprising an imagingagent and a solvent and prior to purification (e.g., by HPLC), thesolution is heated. In a particular embodiment, an imaging agent isreconstituted in a water/acetonitrile mixture and heated (e.g., to atemperature of about 90-100° C.) for about 1 minute, about 3 minutes,about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes,or more. Following heating of the mixture, the solution may beoptionally cooled prior to purification.

E4. Metal Chelation

In some embodiments, an imaging agent according to the present inventiondoes not contain a covalent-bound imaging moiety. In some embodiments, aprovided imaging agent comprises a chelator associated with an imagingmoiety (e.g., ⁶⁴Cu, ⁸⁹Zr, ^(99m)Tc, or ¹¹¹In). In some embodiments, aprovided imaging agent is formed via association of a chelator with animaging moiety. For example, in some embodiments, formation of acompound of Formula (Ia) comprises associating the R⁰ group comprising achelator with an imaging moiety. Conditions for effecting association ofan imaging moiety with a chelator will depend on the type of chelatorbeing used and are well known in the art.

E5. Deprotection

In some embodiments, an imaging agent precursor and/or an imaging agentis deprotected. For example, in embodiments wherein the imaging agentprecursor and/or imaging agent comprises a protected nitrogen functionalgroup (e.g., a protected guanidine), the protected nitrogen functionalgroup may be deprotected.

Those of ordinary skill in the art will be aware of suitable conditionsfor deprotecting a protected nitrogen functional group (e.g., aprotected guanidine). The protecting groups may be remove prior to,simultaneously, and/or subsequent formation of an imaging agent from animaging agent precursor. In some cases, the deprotection occursfollowing formation of the imaging agent.

In some embodiments, suitable conditions comprise exposing a compoundcomprising a protected nitrogen functional group (e.g., guanidine) to anacid. An acid may be added neat or in a solution (e.g., such that theacid is at a concentration of about 0.1 M, about 0.2 M, about 0.3 M,about 0.4 M, about 0.5 M, about 0.75 M, or about 1.0 M). In certainembodiments, a nitrogen-protecting group is t-butyloxycarbonyl, and anacid used for deprotection is trifluoroacetic acid. In certainembodiments, following deprotection, a provided compound is a salt(e.g., a trifluoroacetate salt).

In some embodiments, suitable conditions for deprotection compriseacidic conditions. In certain embodiments, an acid is provided at aratio of about 2:1, about 1:1, about 1:2, about 1:3, or about 1:4compound:acid. In certain embodiments, the pH range for deprotection ofimaging agent precursors such as compounds of Formula (VIII) (oralternatively of protected fluorinated imaging agents of the invention)may be equal to or less than about 4, including equal to or less thanabout 3, equal to or less than about 2, and equal to or less than about1.

In certain embodiments, deprotection conditions may comprise one or moresolvents. Non-limiting examples of solvents are provided herein. Adeprotection reaction may be carried out at any suitable temperature,and in certain embodiments, a deprotection reaction is carried out atroom temperature or above room temperature. The product of adeprotection reaction may be analyzed, isolated, and/or purified usingtechniques known to those of ordinary skill in the art (e.g., columnchromatography, HPLC, NMR, MS, IR, UV/Vis). In some embodiments, theproduct of a deprotection reaction is isolated as a salt (e.g., viafiltration, crystallization). In certain embodiments, the salt is anascorbate salt. In certain embodiments, the salt is a formate salt. Insome embodiments, the salt is a citrate salt. In some embodiments, thesalt is a trifluoroacetate salt.

E6. Purification and Formulation

In some cases, the synthesis, purification, and/or formulation of animaging agent is performed using an automated reaction system optionallycomprising a cassette, wherein the cassette comprises a synthesismodule, a purification module, and/or a formulation module. Automatedreaction systems and cassettes are described herein.

Purification and isolation may be performed using methods known to thoseskilled in the art, including separation techniques like chromatography,or combinations of various separation techniques known in the art, forexample, extractions, distillation, and crystallization. In oneembodiment, high performance liquid chromatography (HPLC) is used with asolvent, or mixture of solvents, as the eluent, to recover the product.In some cases, the eluent includes a mixture of water and acetonitrile,such as a 20:80 water:acetonitrile mixture. The content of water in theeluent may vary from, for example, about 1% to about 30%. In some cases,HPLC purification may be performed using a C18 column. The product maybe analyzed (e.g., by HPLC) to determine yield (e.g., radiochemicalyield) and/or radiochemical purity. The radiochemical purity may begreater than about 50%, about 60%, about 70%, about 80%, about 90%,about 95%, about 97%, about 98%, about 99%, or more. The percent yieldof a product may be greater than 10%, greater than 20%, greater than30%, greater than 40%, greater than 50%, greater than about 60%, greaterthan about 70%, greater than about 75%, greater than about 80%, greaterthan about 85%, greater than about 90%, greater than about 92%, greaterthan about 95%, greater than about 96%, greater than about 97%, greaterthan about 98%, greater than about 99%, or greater. In some embodiments,the radiochemical yield ranges from 15-50%.

The product may be further processed using additional purificationtechniques, such as filtration. In some cases, the imaging agent ispurified using HPLC, to produce a solution of HPLC mobile phase and theimaging agent. The HPLC mobile phase may be subsequently exchanged for asolution of ascorbic acid or a salt thereof, and ethanol solution, byfiltration through a C-18 resin (e.g., C18 Sep-Pak® cartridge). In someembodiments, the solution of the HPLC mobile phase and the imaging agentis filtered through a C-18 resin, where the imaging agent remains on theresin and the other components, such as acetonitrile and/or othersolvents or components, are removed via elution. The C-18 resin may befurther washed with a solution of ascorbic acid or a salt thereof, andthe filtrate discarded. To recover the purified imaging agent, the C-18resin is washed with a solvent, such as ethanol, and the resultingsolution is optionally further diluted with an ascorbic acid solution ora salt thereof, as described herein.

Optionally, the recovered product is combined with one or morestabilizing agents, such as ascorbic acid or a salt thereof. Forexample, a solution comprising the purified imaging agent may be furtherdiluted with a solution of ascorbic acid or a salt thereof. As describedherein, a formulation may be prepared via an automated reaction systemcomprising a cassette.

In some cases, a solution comprising the imaging agent product may besterile filtered (e.g., using a 13 mm diameter, Millipore, Millex PVDF0.22 μm sterilizing filter) into a sterile product vial. The sterileproduct vial may be a commercially available, pre-sterilized unit thatis not opened during the production process, as any imaging agents (orother components) may be aseptically inserted through the septum priorto use. Those of ordinary skill in the art would be able to selectsuitable vials and production components, including commerciallyavailable, pre-sterilized units comprising a 0.22 μm pore size membraneventing filter and quality control sampling syringes.

Following aseptic filtration, individual doses may be filled insyringes, labeled, and shipped to a clinical site. Dosing administrationtechniques, kits, cassettes, methods and systems (e.g., automatedreaction systems) for synthesis of the imaging agent, and testingprocedures are described herein. In some embodiments, the product isdispensed into a 3 or 5 mL syringe and labeled for distribution. Labelsmay be prepared at a radiopharmacy and applied to a syringe shield andshipping container. Additional labels may be provided in the shippingcontainer for inclusion in clinical site records.

F. Uses of Imaging Agents

In another aspect, the present invention provides methods of imaging,including methods of imaging a subject that includes administering acomposition or formulation that includes an imaging agent as describedherein to the subject by injection, infusion, or any other method ofadministration, and imaging a region of interest of the subject. Regionsof interest may include, but are not limited to, the heart, a portion ofthe heart, the cardiovascular system, cardiac vessels, blood vessels(e.g., arteries and/or veins), brain, pancreas, adrenal glands, otherorgans, and tumors.

In some embodiments, methods of this disclosure include (a)administering to a subject a composition that includes an imaging agentas described herein, and (b) acquiring at least one image of at least aportion of the subject. In some cases, the step of acquiring employspositron emission tomography (PET) for visualizing the distribution ofthe imaging agent within at least a portion of the subject. As will beunderstood by those of ordinary skill in the art, imaging using methodsof this disclosure may include full body imaging of a subject, orimaging of a specific body region, organ, or tissue of the subject thatis of interest. For example, if a subject is known to have, or issuspected of having myocardial ischemia, methods of this disclosure maybe used to image the heart of the subject. In some embodiments, imagingmay be limited to the heart or may include the heart and its associatedvasculature.

In some embodiments, imaging agents as described herein are used tomonitor and/or assess certain aspects of the sympathetic nervous system(SNS). The SNS plays a role in normal cardiac regulation and/or thepathogenesis of heart failure development and/or progression. Generally,following myocardial insult (e.g., myocardial infarction, valveregurgitation, hypertension), compensatory activation of the SNS isinduced to help maintain sufficient cardiac output. Sustained elevationof the cardiac SNS can cause elevated cardiac norepinephrine (NE)release, down regulation of the beta1 adrenergic receptor, and/or downregulation of the NE transporter (NET), which can result in spillover ofNE. Elevated levels of NE can be attributed to cardiac myocytehypertrophy, fibroblast activation, collagen deposition, and/or myocyteapoptosis, which can result in ventricle remodeling and/orsusceptibility to arrhythmia.

In some embodiments, assessment of the changes and/or the presence of aneurotransmitter in a subject, and certain parameters relating to theneurotransmitter provides feedback relating to cardiac events. Forexample, assessment of NET in a subject can be used to provide feedbackrelating to cardiac events and/or cardiac exposure to NE. In some cases,the neurotransmitter is a monoamine other than NE.

In some embodiments, the neurotransmitter is NE. Utilizing an imagingagent that targets NET permits imaging of the location, concentration,density, and/or distribution of NETs and also can be used to detectchanges in NETs over time, for example, by acquiring a first NET imagein a subject or region of a subject; obtaining a subsequent NET image ofthe subject or the region of the subject and comparing the first andsubsequent images. Differences between the images can provideinformation on the change in NET status in the subject or region of thesubject. Changes in a NET parameter (e.g., location, density,concentration, and/or distribution) over time may be assessed andcorrelated with disease onset, progression, and/or regression. In someembodiments, a method comprises administering a dose of apharmaceutically acceptable composition to a subject, and acquiring atleast one image of a portion of the subject, wherein the image allowsfor the assessment and/or detection of NET in the subject. In somecases, the detection comprises detection of the level (e.g.,concentration) of NET, detection of the density of NET, detection of NETfunction, and/or detection of the localization of NET.

In some embodiments, changes in NET (e.g., density, localization,concentration, function) may be used to assess the presence and/orabsence of a condition, disease, and/or disorder. For example, in somecases, changes in NET may be used to assess cardiac sympatheticinnervation and/or myocardial sympathetic function in a subject. Forexample, an increase or decrease in NET concentration in a portion ofthe subject (e.g., heart) may indicate the cardiac sympatheticinnervation in that portion of the subject. In some cases, subjects withimpaired NET functions are correlated with heart failure and/or rapidmyocardial reorganization.

In some embodiments, an imaging agent that targets NET may also be usedto observe, estimate, and/or quantify localized blood flow to tissue.More specifically, there may be instances in which the level of imagingagent (or radioactivity) observed in the myocardium, is decreasedcompared to normal or below threshold. There may be various causes ofthis decreased signal, one of which may be reduced blood flow to andthrough the myocardium. In order to determine the cause, the subject maybe imaged using a different imaging agent and/or a different imagingmodality suitable for detecting blood flow. Comparison of imagesobtained using the different methods can reveal whether the decrease orabsence of signal from the imaging agent that targets NET isattributable to blood flow rather than to a difference in NET level,activity and the like. In other embodiments of the invention, themyocardium may be imaged serially, for example immediately afteradministration of the imaging agent, in order to observe movement of theimaging agent into the heart. Such serial images should yieldinformation about blood flow through the heart. Later images are alsoobtained as these reveal a more steady state of blood flow into and outof the heart as well as blood retention in the heart. In this way,alterations in global, local, or regional blood flow may bedistinguished from local or regional changes in NET density,localization, concentration, and function as described above.

In some embodiments, an imaging agent that targets NET is used to assessthe ability of a therapeutic agent and/or treatment to modify NET. Forexample, images acquired from a subject administered an imaging agentbefore therapeutic treatment can be compared to images acquired from thesame subject after therapeutic treatment of the subject to determine ifthe treatment has affected the location, concentration, and/or densityof NET for the subject. Similarly, images at different times and/orbefore and after treatment can be used to detect changes in NET in asubject over time and/or with treatment.

In some aspects, global images (e.g., global NET images) are acquired,and in other aspects of the invention, regional images (e.g., regionalNET images) are acquired following administration of an imaging agentthat targets NET, wherein a global image is an image of all orsubstantially all of an organ (e.g., heart, kidney, pancreas), and aregional image is an image of only a portion of an organ. Images can beacquired using an image collection system such as a PET system, a SPECTsystem, or any other suitable imaging system.

In some embodiments, images may be acquired over a single time interval,and in other embodiments, they may be acquired as a series of images ofthe same or different acquisition durations beginning either at the timeof administration or at a later time.

In some embodiments, the imaging agents may be used to image cardiacinnervation. In some embodiments, agents for imaging cardiac innervationmay be utilized in the assessment of heart failure. In certainembodiments, the methods comprise an assessment of heart failureprogression in a subject, wherein the assessment may includedetermination of the effectiveness of a treatment regimen. In somecases, the treatment regimen may include a beta blocker. In other cases,the treatment may require implantation of a pacemaker or implantablecardioverter-defibrillator (ICD). In certain embodiments, agents forimaging cardiac innervation may be useful in the prediction of a timecourse for heart failure disease progression.

In some embodiments, methods of diagnosing or assisting in diagnosing adisease or condition, assessing efficacy of a treatment of a disease orcondition, or imaging of a subject with a known or suspectedcardiovascular disease or condition changing sympathetic innervationsare provided. A cardiovascular disease can be any disease of the heartor other organ or tissue supplied by the vascular system. The vascularsystem includes coronary arteries, and all peripheral arteries supplyingthe peripheral vascular system and the brain, as well as veins,arterioles, venules, and capillaries. In cases, cardiac innervation maybe examined, as abnormalities in cardiac innervation have beenimplicated in the pathophysiology of many heart diseases, includingsudden cardiac death, congestive heart failure, diabetic autonomicneuropathy, myocardial ischemia, and cardiac arrhythmias. Othernon-limiting examples of cardiovascular diseases of the heart includediseases such as coronary artery disease, myocardial infarction,myocardial ischemia, angina pectoris, congestive heart failure,cardiomyopathy (congenital or acquired), arrhythmia, or valvular heartdisease. In some embodiments, the methods disclosed herein are usefulfor monitoring and measuring cardiac innervation. For example, a methoddescribed herein can determine the presence or absence of cardiacinnervation. Conditions of the heart may include damage, not brought onby disease but resulting from injury e.g., traumatic injury, surgicalinjury. Methods described herein can be used in some embodiments todetermine global or regional changes in cardiac sympathetic innervation.

In some cases, a subject whom an imaging agent as described herein maybe administered may have signs or symptoms suggestive of a disease orcondition associated with abnormalities in cardiac innervation. In somecases, use of the imaging agent can be used to diagnose early orpre-disease conditions that indicate that a subject is at increased riskof a disease. Imaging methods described herein may be used to detectcardiac innervation in subjects already diagnosed as having a disease orcondition associated with abnormalities in cardiac innervation, or insubjects that have no history or diagnosis of such a disease orcondition. In other instances, the methods may be used to obtainmeasurements that provide a diagnosis or aid in providing a diagnosis ofa disease or condition associated with abnormalities in cardiacinnervation. In some instances, a subject may be already undergoing drugtherapy for a disease or condition associated with abnormalities incardiac innervation, while in other instances a subject may be withoutpresent therapy for a disease or condition associated with abnormalitiesin cardiac innervation. In some embodiments, the method may be used toassess efficacy of a treatment for a disease or condition. For example,the heart can be visualized using contrast/imaging agents describedherein before, during, and/or after treatment of a condition affectingthe heart of a subject. Such visualization may be used to assess adisease or condition, and aid in selection of a treatment regimen, e.g.therapy, surgery, medications, for the subject.

In some embodiments, an imaging agent as described herein is employedfor determining the presence or absence of a tumor in a subject. In someembodiments, the tumor is a NET-expressing tumor. In some embodiments,an imaging agent of the invention is employed for determining theresponse to therapy of a tumor in a subject. Methods for determining thepresence of a tumor and/or for determining the response to therapy of atumor in a subject can follow the same or similar methods as describedfor methods of imaging a subject.

Regional denervated myocardium may exhibit comparable effectiverefractory period (ERP) to normal innervated area but increasedsensitivity to NE induced ERP shortening, or increased ERP but similarsensitivity to NE induced ERP shortening. In addition, heterogeneity ofsympathetic innervation may render the heart abnormalelectrophysiologically and may increase sensitivity to drugs whichinteract with cardiac ion channel conductance, such as antiarrhythmicdrugs. In some cases, the presence of cardiac denervation in a subjectmay increase the subject's sensitivity and/or cardiac risk toantiarrhythmic agent treatments that induce electrophysiologicalchanges. In some embodiments, an imaging agent as described herein maybe used to determine whether a subject has an enhanced cardiac risk toan antiarrhythmic agent treatment, including, for example,antiarrhythmic agents that induce electrophysiological changes. Forexample, in some embodiments, the images obtained from a subject usingan imaging agent as described herein may be used to aid in the selectionof an antiarrhythmic agent and/or may be used to determine anappropriate dose and/or adjustment of a dose (e.g., increase ordecrease) of an antiarrhythmic agent for administration to the subjectby determining the presence, absence, and/or extent of cardiacdenervation. If cardiac denervation is present, an antiarrhythmic agentwhich does not induce electrophysiological changes may be administeredand/or the dose of an antiarrhythmic agent which is known to induceelectrophysiological changes may be reduced. In some embodiments, theelectrophysiological change comprise QT prolongation. In someembodiments, a reduced dose of an antiarrhythmic agent may be determinedvia a dose titration, wherein the subject is monitored during and/orfollowing administration of the drug to determine or assess the presenceof electrophysiological changes depending on the dose of theantiarrhythmic agent.

Antiarrhythmic agents that induce electrophysiological changes in theheart include, for example, agents known to block ion channels (e.g.,calcium-, sodium-, or potassium-channels). Non-limiting examples of suchagents include, but are not limited to, dofetilide, ibutilide,amiodarone, sotalol, and dronedarone. The invention contemplates the useof reduced doses of these agents in some instances including for examplewhere cardiac denervation exists.

Antiarrhythmic agents that do not induce electrophysiological changes inthe heart and/or that induce minimal, electrophysiological changes inthe heart include, for example, some beta-blockers. Non-limiting of suchagents include, but are not limited to, opranolol, esmolol, timolol,metoprolol, atenolol, and bisoprolol. The invention contemplates the useof these agents in some instances including for example where cardiacdenervation exists.

Other non-limiting examples of antiarrhythmic agent include quinidine,procainamide, disopyramide, lidocaine, phenytoin, mexiletine, tocainide,flecainide, propafenone, moricizine, verapamil, diltiazem, adenosine,digoxin, and magnesium sulfate. The invention contemplates the use ofreduced doses of these agents in some instances including for examplewhere cardiac denervation exists.

In some embodiments, an imaging agent as described herein may be used todetermine a subject's cardiac risk associated with innervationdysfunction.

In some embodiments, an imaging agent as described herein is used as animaging agent in combination with positron emission tomography (PET) orwith other imaging methods including, but not limited to, single photonemission computed tomography (SPECT) imaging. In some cases, PET imagingmay be used in cardiac sympathetic neuronal imaging in a subjectfollowing administration of the imaging agent to the subject. Forexample, the imaging agent may be administered to a subject and imagedin the subject using PET. As will be known to those of ordinary skill inthe art, PET is a non-invasive technique that allows serial images andmeasurements to be obtained in a single subject over a time period. PETimaging used may be carried out using known systems, methods, and/ordevices. In some embodiments, PET imaging is conducted using a cardiacimaging system. A cardiac imaging system may include PET imagingfunctionality; and a control unit configured to drive the imagingfunctionality to perform a PET imaging procedure on a portion of thesubject of interest before, during, and/or after administration of theimaging agent to the subject. In some cases, the control unit isconfigured to drive the imaging functionality to perform a PET imagingprocedure. The control unit may comprise a computer system and/orsoftware. In such a case, the computer system may be programmed orconfigured to execute the required methods for acquiring and/oranalyzing the images. Further, the system may include a data storagedevice that is readable by a machine, embodying a set of instructionsexecutable by the machine to perform the required methods of acquiringand/or analyzing the images.

Imaging systems (e.g., cardiac imaging systems) and components thereofwill be known to those of ordinary skill in the art. Many imagingsystems and components (e.g., cameras, software for analyzing theimages) are known and commercially available, for example, a SiemensBiograph-64 scanner or other scanner suitable for imaging. In someembodiments, image data is acquired in list mode, and such list data maybe used to create static, dynamic, or gated images. An appropriateperiod of time for acquiring images can be determined by one of ordinaryskill in the art, and may vary depending on the cardiac imaging system,the imaging agent (e.g., amount administered, composition of the imagingagent, subject parameters, area of interest). As used herein, a “periodof acquiring images” or an“image acquisition period” may be a period oftime for obtaining a single continuous image, and/or may be a periodduring which one or more individual discrete images are obtained. Thus,a period of image acquisition can be a period during which one or moreimages of one or more regions of a subject are acquired.

The term “list mode,” as used herein, is given its ordinary meaning inthe art. With respect to PET, list mode is a form in which the data thatis used to create a PET image can be initially collected. In list mode,each of or a portion of coincidence events (i.e., each of a portion ofdetected photon pairs) generates an entry in a list of events. Eachentry includes various information including, but not limited to, whichdetectors were involved, the energy of the photons detected, the time ofdetection, and/or whether there was a cardiac gating mark. Theinformation can be converted into one or more images by the process ofrebinning and/or histogramming, in which all or a portion of the eventsfor each pair of detectors is summed, followed by the resulting set ofprojections (e.g., in the form of a sinogram wherein for each slice,each horizontal line in the sinogram represents the projections forcoincidences at a given angle). List mode may be contrasted with“histogram mode” in which the summations are completed duringacquisition so that the only raw data is the sinogram. In someembodiments, histogram mode may be employed.

In embodiments where more than one type of imaging agent is adminsteredto a subject, a second imaging agent may be administered to the subject,followed by acquisition of at least one second image. The second imagingagent may be administered to the subject after any suitable period oftime has elapsed following administration of the first imaging agentand/or acquisition of the at least one first image. In some cases, thetime between administration of the first imaging agent and the secondimaging agent is about between about 1 minute and about 48 hours, orbetween about 1 hour and about 48 hours, or between about 1 minute andabout 24 hours, or between about 1 hour and 24 hours, or between about10 minutes and about 12 hours, or between about 30 minutes and about 8hours, or between about 30 minutes and about 6 hours, or between 30minutes and about 3 hours, or between about 30 minutes and about 2hours, or between about 1 hour and about 6 hours. In some cases, thetime between administration of the first imaging agent and the secondimaging agent is at least about or about 1 minute, at least about orabout 5 minutes, at least about or about 10 minutes, at least about orabout 15 minutes, at least about or about 20 minutes, at least about orabout 30 minutes, at least about or about 45 minutes, at least about orabout 60 minutes, at least about or about 90 minutes, at least about orabout 2 hours, at least about or about 3 hours, at least about or about4 hours, at least about or about 5 hours, at least about or about 6hours, at least about or about 8 hours, at least about or about 10hours, at least about or about 12 hours, at least about or about 18hours, at least about or about 24 hours, or greater.

Those of ordinary skill in the art will be aware of suitable periods oftime for acquiring an image. In some embodiments, a period of imageacquisition after administration of an imaging agent to a subject may bebetween about 0 seconds and about 60 minutes, between about 1 minute andabout 30 minutes, between about 5 minutes and about 20 minutes, or atleast about 1 minute, at least about 3 minutes, at least about 5minutes, at least about 6 minutes, at least about 7 minutes, at leastabout 8 minutes, at least about 9 minutes, at least about 10 minutes, atleast about 15 minutes, at least about 20 minutes, at least about 30minutes, at least about 45 minutes, at least about 60 minutes, at leastabout 90 minutes, at least about 2 hours, at least about 3 hours, atleast about 4 hours, at least about 5 hours, or greater. In someembodiments, a period of image acquisition may begin prior toadministration of the imaging agent to a subject. For example, a periodof image acquisition may begin more than about 10 minutes, about 5minutes, about 4, minutes, about 3 minutes, about 2 minutes, about 1minute, or about 0 minutes prior to administration of the imaging agentto the subject. In some embodiments, imaging may be continuous over theimaging period of time, or images may be acquired at intervals such asin periodic or gated imaging.

In some embodiments, an imaging agent as described herein is provided inethanol/ascorbic acid. In some embodiments, an imaging agent asdescribed herein is provided as a composition comprising ethanol,ascorbic acid or a salt thereof (e.g., as sodium ascorbate), and water.In some cases, the composition comprises less than or about 20 weight %ethanol, less than or about 15 weight % ethanol, less than or about 10weight % ethanol, less than or about 8 weight % ethanol, less than orabout 6 weight % ethanol, less than or about 5 weight % ethanol, lessthan or about 4 weight % ethanol, less than or about 3 weight % ethanol,or less ethanol. In some cases, the composition comprises less than orabout 100 mg/mL, less than or about 75 mg/mL, less than or about 60mg/mL, less than or about 50 mg/mL, less than or about 40 mg/mL, lessthan or about 30 mg/mL, less than or about 20 mg/mL, less than or about10 mg/mL, or less ascorbic acid or a salt thereof (e.g., sodiumascorbate) in water. A non-limiting, exemplary formulation of an imagingagent includes about 5 weight % ethanol and about 50 mg/ml ascorbicacid. As will be understood by those of ordinary skill in the art, inthe presence of ascorbic acid, at least a portion of the imaging may bepresent as the ascorbate salt of the imaging agent.

Additional components of a composition comprising an imaging agent asdescribed herein may be selected depending on the mode of administrationto the subject. Various modes of administration will be known to one ofordinary skill in the art which effectively deliver the pharmacologicalagents as described herein to a desired tissue, cell, organ, or bodilyfluid. In some embodiments, an imaging agent as described herein isadministered intravenously (e.g., intravenous bolus injection) usingmethods known to those of ordinary skill in the art. As used herein, adose that is “administered to a subject” means an amount of the imagingagent that enters the body of the subject.

In some embodiments, the volume of the administered imaging agent may bebetween 0 and about 3 mL, between about 3 mL and about 5 mL, or betweenabout 5 mL and about 10 mL.

In some embodiments, due to factors such as partial retention of imagingagent in a syringe, tubing, needles, or other equipment used toadminister the imaging agent to a subject, the amount of an imagingagent that is measured or determined to be in the a syringe or otherequipment prepared for administration may be more than the amount in thedose that is administered to the subject. In some embodiments, aninjection of an imaging agent is followed by a flushing injection ofnormal saline into the subject, using the same tubing, needle, port,etc., used for administration of the imaging agent.

Flushing may be performed immediately following administration of theimaging agent, or up to about 1 min, about 2 min, about 3 min, about 5min, or more after the administration. In some embodiments, flushing maybe performed between 0 and 10 seconds, between 10 seconds and 25seconds, or between 25 seconds and 60 seconds.

The volume of saline or other agent for flushing may be up to about 5ml, about 6 ml, about 7 ml, about 8 ml, about 9 ml, about 10 ml, about15 ml, about 20 ml, or more. As will be understood by those of ordinaryskill in the art, in embodiments where the imaging agent is administeredusing a syringe or other container, the true amount of imaging agentadministered to the subject may be corrected for any imaging agent thatremains in the container. For example, the amount of radioactivityremaining in the container, and tubing and needle or delivery instrumentthat carried the imaging agent from the container and into the subjectcan be determined after the imaging agent has been administered to thesubject and the difference between the starting amount of radioactivityand the amount remaining after administration indicates the amount thatwas delivered into the subject. In some cases, the container orinjection device (e.g., catheter, syringe) may be rinsed with a solution(e.g., saline solution) following administration of the imaging agent.

A composition of an imaging agent as described herein for injection maybe prepared in an injection syringe. Imaging agents may be prepared by aradiopharmacy (e.g., using the methods described herein) and/or a PETmanufacturing center and provided to a health-care professional foradministration. A dose of the imaging agent may be diluted with saline(e.g., as described herein), if needed to obtain a practical dosevolume. For example, if the activity concentration of the imaging agentis so high that only about 0.1 mL is needed for an appropriate dose fora subject, the solution can be diluted, e.g., with sterile saline, sothe syringe contains about 0.5 ml to about 6 ml or more ml of theimaging agent solution for administration. In some embodiments, aninjection volume for the imaging agent is between about 0.5 and about 5ml, about 1 and about 4 ml, about 2 and about 3 ml, at least about 0.5ml, about 1 ml, about 2 ml, about 3 ml, about 4 ml, about 5 ml, about 6ml, about 7 ml, about 8 ml, about 9 ml, about 10 ml, or more. Those ofskill in the art will recognize how to dilute an imaging agent toproduce a sufficient dose volume for administration. In some aspects, animaging agent is provided in a container such as a vial, bottle, orsyringe, and may be transferred, as necessary, into a suitablecontainer, such as a syringe for administration.

Components of a composition comprising an imaging agent as describedherein may be selected depending on the mode of administration to thesubject. Various modes of administration that effectively deliverimaging agents as described herein to a desired tissue, cell, organ, orbodily fluid will be known to one of ordinary skill in the art. In someembodiments, the imaging agent is administered intravenously (e.g.,intravenous bolus injection) using methods known to those of ordinaryskill in the art.

The useful dosage of the imaging agent to be administered and theparticular mode of administration will vary depending upon such factorsas age, weight, and particular region to be imaged, as well as theparticular imaging agent used, the diagnostic use contemplated, and theform of the formulation, for example, suspension, emulsion, microsphere,liposome, or the like, as described herein, and as will be readilyapparent to those skilled in the art.

Based on dosing studies, the desirable maximum dose administered to asubject may be based on determining the amount of imaging agent(s) asdescribed herein, which limits the radiation dose to about 5 rem to thecritical organ (e.g., urinary bladder) and/or about 1 rem effective dose(ED) or lower, as will be understood by those of ordinary skill in theart. In embodiments where more than one imaging agent is administered tothe subject, the desirable maximum dose administered to a subject may bebased on determining the amounts of the first imaging agent and/or thesecond imaging agent, which limits the total radiation dose to about 5rem to the critical organ (e.g., urinary bladder) and/or about 1 remeffective dose (ED) or lower. In some embodiments, a desirable dose ofimaging agent(s) may be less than or equal to about 50 mCi, less than orequal to about 40 mCi, less than or equal to about 30 mCi, less than orequal to about 20 mCi, less than or equal to about 15 mCi, less than orequal to about 14 mCi, less than or equal to about 13 mCi, less than orequal to about 12 mCi, less than or equal to about 11 mCi, or less thanor equal to about 10 mCi over a period of time of up to about 10minutes, about 30 minutes, about 1 hour, about 2 hours, about 6 hours,about 12 hours, about 24 hours, or about 48 hours. In some embodiments,the dose of each imaging agent administered per session or day is about1 mCi, about 2 mCi, about 3 mCi, about 4 mCi, about 5 mCi, about 6 mCi,about 7 mCi, about 8 mCi, about 9 mCi, about 10 mCi, about 11 mCi, about12 mCi, about 13 mCi, about 14 mCi, or any range therein.

In some embodiments, studies may also be performed using an agentspecialized for tissue blood flow using methods known to those familiarwith the art. The images from these studies may then be used todistinguish abnormalities seen in images due to changes in NET fromthose due to alterations of global, regional or local blood flow.

G. Methods for Assessing Perfusion and Innervation Mismatch

In some embodiments, methods and compositions for assessing perfusionand innervation mismatch in a portion of a subject, for example, a humansubject, are provided. In some embodiments, the methods and compositionsmay be employed for assessing perfusion and innervation mismatch in asubject following a tissue insult. In some embodiments, the tissueinsult is a cardiac insult, for example, a myocardial infarction. Insome embodiments, the portion of the subject being assessed forperfusion/innervation mismatch is the heart or a portion of the heart.Other regions of interest may include, but are not limited to, thecardiovascular system, cardiac vessels, blood vessels (e.g., arteriesand/or veins), brain, pancreas, adrenal glands, other organs, andtumors.

In some embodiments, a method comprises administering to a subject afirst imaging agent and acquiring at least one first image of a portionof the subject. A second imaging agent is then administered to thesubject and at least one second image of the same portion of the subjectis acquired. In some embodiments, the first imaging agent is employed toimage perfusion (e.g., cardiac perfusion), and the second imaging agentis employed to image innervation (e.g., cardiac innervation). In otherembodiments, the first imaging agent is employed to image innervationand the second imaging agent is employed to image perfusion. The regionof mismatch of perfusion and innervation is based at least in part onthe first image and the second image. Imaging agents which may be usedto image innervation or perfusion will be known to those of ordinaryskill in the art and are described herein (e.g., see Sections G1 andG2).

In some embodiments, the regional mismatch of perfusion and innervationin a portion of a subject may be determined by determining thedifference in uptake of the first imaging agent versus uptake of thesecond imaging agent in a portion of the subject (e.g., the heart). As anon-limiting example, the first imaging agent may be an imaging agentwhich is employed for imaging perfusion (e.g., cardiac perfusion).Accordingly, the areas in the at least one first image which indicateuptake of the first imaging agent are areas in which there is perfusion.The second imaging agent may be an imaging agent which is employed forimaging innervation (e.g., cardiac innervation). The areas in the atleast one second image which indicate uptake of the second imaging agentare the areas in which there is innervation. The difference in the areasof uptake between the first image and the second image are areas inwhich there is perfusion (e.g., as indicated by uptake of the firstimaging agent) but in which there is decreased or no innervation (e.g.,as indicated by lack of or decreased uptake of the second imagingagent).

Generally, the mismatch is the observed difference in the level ofinnervation and the level of perfusion in a portion of the subject. Themismatch between innervation and perfusion areas, as determined inaccordance with the invention, may be expressed or quantified using anysuitable technique. In some embodiments, the difference between uptakeof the first imaging agent and the uptake of the second imaging agentmay be expressed as a percent of defect size in a portion of thesubject. For example, in embodiments where the portion of the subject isa the heart or a portion of the heart, the difference between uptake ofthe first imaging agent and the uptake of the second imaging agent maybe expressed as the percent defect size in the left ventricle (LV). Insome cases, the difference between the uptake of the first imaging agentand the second imaging agent may be expressed as a ratio. In someembodiments, the mismatch may be determined and/or quantified usingpolar maps of the images. In some embodiments, the defect areas forperfusion and/or innervation may be defined as those regions in whichperfusion and/or innervation is less than 50% of the maximum value ofperfusion and/or innervation in a portion of a subject. In someembodiments, the mismatch may be determined by subtracting the perfusiondefect from the innervation defect or otherwise quantifying thedifference between the perfusion and innervation areas. In someembodiments, the mismatch may be determined using software (e.g.,MunichHeart™; see, for example, Nekolla et al., Eur J Nucl Med 1998;25(9):1313-21; Haas et al., J Am Coll Cardiol 1997; 30(7):1693-700;Nekolla et al., J Nucl Med 1999; 40(5):5P; Hattori, et al., Europ. J.Nucl. Med. 2001; 28:221-229; Klein et al., Circulation 105: 162-167(2002); Ibrahim et al., J. Am. Coll. Cardiol. 2000; 6; 39(5):864-70).

Those of ordinary skill in the art may be aware of suitable methods andtechniques for imaging a subject, for example, a human subject In someembodiments, methods of imaging comprise (a) administering to a subjecta composition that includes an imaging agent, and (b) acquiring at leastone image of at least a portion of the subject. In some cases, the stepof acquiring an image employs positron emission tomography (PET) forvisualizing the distribution of the imaging agent within at least aportion of the subject. As will be understood by those of ordinary skillin the art, imaging methods may include full body imaging of a subject,or imaging of a specific body region, organ, or tissue of the subjectthat is of interest. For example, if a subject is known to have, or issuspected of having a cardiac insult (e.g., myocardial infarction), themethods of this disclosure may be used to image the heart of thesubject. In some embodiments, imaging may be limited to the heart or mayinclude the heart and its associated vasculature. Regions of interestmay include, but are not limited to, the heart, a portion of the heart,the cardiovascular system, cardiac vessels, blood vessels (e.g.,arteries and/or veins), brain, pancreas, adrenal glands, other organs,tumors, and other vascularized soft tissues. A particular region ofinterest is the heart or a portion of the heart.

In some embodiments, the mismatch is determined in a subject following atissue insult. In such embodiments, the portion of the subject beingimaged may be the portion of the subject that sustained the tissueinsult and/or that was affected by the tissue insult. In someembodiments, the tissue insult is an insult which results in denervationof the tissue. In some embodiments, the tissue insult is an insult whichresults in a perfusion defect and/or denervation of the tissue. In someembodiments, the tissue insult is an insult which results in a perfusiondefect and denervation of the tissue. In some embodiments, the tissueinsult is a cardiac insult. In some embodiments, the cardiac insult is amyocardial infarction, congestive heart failure, diabetic autonomicneuropathy, myocardial ischemia, and cardiac arrhythmias. Those ofordinary skill in the art will be aware of other tissues which may havean innervation defect including, for example, sympathetically innervatedtissues. In some cases, the tissue is a tissue which expresses NET.Non-limiting examples of tissues which express NET include pancreas,adrenal glands, thyroid, and tumors (e.g., neuroendocrine tumors,pheochromocytoma tumors). Non-limiting examples of tissue insultsinclude diseases which affect the tissue (e.g., autoimmune disease(e.g., Graves disease), diabetes, hyperthyroidism, hypothyroidism, acutepancreatitis, etc.), a tumor in the tissue, and/or trauma of the tissue(e.g., blunt force trauma, iatrogenic injury). It should be understood,that while much of the following discussion focuses on the heart or aportion of the heart and/or a tissue insult comprising a cardiac insult(e.g., myocardial infarction), this is by no means limiting, and theinvention contemplates imaging and assessing mismatch in other tissuesand regions of the body, and those of ordinary skill in the art will beable to apply the teachings herein to other tissues and/or tissueinsults.

The mismatch between innervation and perfusion may be determined at anysuitable time. In some embodiments, the mismatch is determined at asingle time point following a tissue insult (e.g., myocardialinfarction). In some cases, the mismatch is determined at a time pointnear to the time at which the tissue insult occurred. Without wishing tobe bound by theory, determining the mismatch at a time point close tothe time at which the tissue insult occurred may provide a betterindication of the treatment and/or diagnosis for the subject as thetissue may reinnervate over time. In some cases, the difference in themismatch is determined within about 6 months, about 5 months, about 4months, about 3 months, about 2 months, about 1 month, about 4 weeks,about 3 weeks, about 2 weeks, about 1 week, about 7 days, about 6 days,about 5 days, about 4 days, about 3 days, about 2 days, about 1 days,about 24 hours, about 20 hours, about 18 hours, about 16 hours, about 14hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours,about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1hour, about 50 minutes, about 40 minutes, about 30 minutes, about 20minutes, about 10 minutes, about 5 minutes, about 4 minutes, about 3minutes, about 2 minutes, or about 1 minute of the tissue insult. Insome cases, the mismatch is determined within 4 weeks of the tissueinsult. In some cases, the mismatch is determined within between about 1week and about 6 months, between about 1 week and about 5 months,between about 1 week and about 4 months, between about 1 week and about3 months, between about 1 week and about 2 months, between about 1 weekand about 1 month, between about 1 week and about 4 weeks, between about2 weeks and about 2 months, between about 2 weeks and about 6 weeks, orbetween about 2 weeks and about 4 weeks of the tissue insult.

In other embodiments, the mismatch may be determined at multiple timepoints following a tissue insult (e.g., myocardial infarction). In somecases, the change in the mismatch over time may be useful in determininga course of treatment and/or a diagnosis following a tissue insult. Insome cases, the change or lack of change in mismatch over time mayindicate the effectiveness or lack of effectiveness, respectively, of acourse of treatment being administered to the subject. For example, adecrease in the region of mismatch over time may indicate reinnervationof the tissue, and thus, may indicate that the course of treatment maybe effective. As another example, a lack of change in the region ofmismatch over time may indicate lack of reinnervation of the tissue andthus, the course of treatment that the subject is undergoing is noteffective and/or another course of treatment may be warranted and/or thetreatment should be continued. The region of mismatch may be determined2 times, 3 times, 4 times, 5 times, 6 times, 8 times, 10 times, or 12times within about 4 weeks, about 2 months, about 3 months, about 4months, about 5 months, about 6 months, about 7 months, about 8 months,about 9 months, about 10 months, about 11 months, about 1 year, about 2years, about 3 years, about 4 years, or about 5 years following thetissue insult (e.g., myocardial infarction). The mismatch may bemonitored at regular frequency or irregular frequency.

In some embodiments, methods of diagnosing or assisting in diagnosing adisease or condition, assessing efficacy of a treatment of a disease orcondition, or imaging of a subject with a known or suspectedcardiovascular disease or condition changing sympathetic innervationsare provided. A cardiovascular disease can be any disease of the heartor other organ or tissue supplied by the vascular system. The vascularsystem includes coronary arteries, and all peripheral arteries supplyingthe peripheral vascular system, as well as veins, arterioles, venules,and capillaries. In cases where cardiac innervation and cardiacperfusion are examined, differences in cardiac innervation and perfusionmay be implicated in the pathophysiology of many heart diseases,including sudden cardiac death, congestive heart failure, diabeticautonomic neuropathy, myocardial ischemia, and cardiac arrhythmias. Insome embodiments, the methods disclosed herein are useful for monitoringand measuring mismatch between cardiac innervation and perfusion.Methods described herein can be used in some embodiments to determineglobal or regional changes in differences between cardiac innervationand perfusion.

In some cases, a subject whom an imaging agent as described herein isadministered has signs or symptoms suggestive of a disease or conditionassociated with a mismatch in innervation and perfusion. Imaging methodsdescribed herein may be used to detect innervation and/or perfusion insubjects already diagnosed as having a disease or condition associatedwith a mismatch in innervation and perfusion, or in subjects that haveno history or diagnosis of such a disease or condition. In otherinstances, the methods is used to obtain measurements that provide adiagnosis or aid in providing a diagnosis of a disease or conditionassociated with a mismatch in innervation and perfusion. In someinstances, a subject is already undergoing drug therapy for a disease orcondition associated with a mismatch in innervation and perfusion, whilein other instances a subject is without present therapy for a disease orcondition associated with a mismatch in innervation and perfusion. Insome embodiments, the method is used to assess efficacy of a treatmentfor a disease or condition. For example, the heart can be visualizedusing contrast/imaging agents described herein before, during, and/orafter treatment of a condition affecting the heart of a subject. Suchvisualization may be used to assess a disease or condition and aid inselection of a treatment regimen, e.g. therapy, surgery, or medication,for the subject.

In some embodiments, an imaging agent as described herein is used as animaging agent in combination with positron emission tomography (PET) orwith other imaging methods including, but not limited to, single photonemission computed tomography (SPECT) imaging. In some cases, PET imagingis used in innervation and/or perfusion imaging in a subject followingadministration of an imaging agent to the subject. For example, theimaging agent may be administered to a subject and imaged in the subjectusing PET. As will be known to those of ordinary skill in the art, PETis a non-invasive technique that allows serial images and measurementsto be obtained in a single subject over a time period. PET imaging usedmay be carried out using known systems, methods, and/or devices, asdescribed herein. In some embodiments, PET imaging is conducted using acardiac imaging system. A cardiac imaging system may include PET imagingfunctionality; and a control unit configured to drive the imagingfunctionality to perform a PET imaging procedure on a portion of thesubject of interest before, during, and/or after administration of theimaging agent to the subject. In some cases, the control unit isconfigured to drive the imaging functionality to perform a PET imagingprocedure. The control unit may comprise a computer system and/orsoftware. In such a case, the computer system may be programmed orconfigured to execute the required methods for acquiring and/oranalyzing the images. Further, the system may include a data storagedevice that is readable by a machine, embodying a set of instructionsexecutable by the machine to perform the required methods of acquiringand/or analyzing the images.

G1. Perfusion Imaging Agents

Some embodiments of the present invention comprise an imaging agent forimaging perfusion (e.g., cardiac perfusion). Those of ordinary skill inthe art will be aware of imaging agents which are capable of imagingperfusion.

In some embodiments, an imaging agent for imaging perfusion (e.g.,cardiac perfusion) may be a Complex-1 inhibitor. Complex 1 (“MC-1”) is amembrane-bound protein complex of 46 dissimilar subunits. This enzymecomplex is one of three energy-transducing complexes that constitute therespiratory chain in mammalian mitochondria. This NADH-ubiquinoneoxidoreductase is the point of entry for the majority of electrons thattraverse the respiratory chain, eventually resulting in the reduction ofoxygen to water (Q. Rev. Biophys. 1992, 25, 253-324). Mitochondria aremembrane-enclosed organelles distributed through the cytosol of mosteukaryotic cells. Mitochondria are especially concentrated in myocardialtissue. Examples of inhibitors of MC-1 include deguelin, piericidin A,ubicidin-3, rolliniastatin-1, rolliniastatin-2 (bullatacin), capsaicin,pyridaben, fenpyroximate, amytal, MPP+, quinolines, and quinolones (BBA1998, 1364, 222-235). Studies have shown that interrupting the normalfunction of mitochondria could advantageously concentrate certaincompounds in the mitochondria, and hence in the mitochondria-richmyocardial tissue. Compounds that include an imaging moiety (e.g., ¹⁸F)can be useful in determining such a build-up of compounds and may beuseful for imaging perfusion. Accordingly, in some embodiments, animaging agent for imaging perfusion (e.g., cardiac perfusion) binds tothe mitochondrial Complex I of the electron transport chain with highaffinity (e.g., the imaging agent may exhibit selective uptake to theheart due to the high density of mitochondria in the myocardium).

In some embodiments, an imaging agent for imaging perfusion comprisesthe formula:

wherein:

J is selected from the group consisting of N(R²⁸), S, O, C(═O), C(═O)O,NHCH₂CH₂O, a bond, and C(═O)N(R²⁷);

when present, K is selected from the group consisting of hydrogen,alkoxyalkyl optionally substituted with an imaging moiety, alkyloxyoptionally substituted with an imaging moiety, aryl optionallysubstituted with an imaging moiety, C₁-C₆ alkyl optionally substitutedwith an imaging moiety, heteroaryl optionally substituted with animaging moiety, and an imaging moiety;

when present, L is selected from the group consisting of hydrogen,alkoxyalkyl optionally substituted with an imaging moiety, alkyloxyoptionally substituted with an imaging moiety, aryl optionallysubstituted with an imaging moiety, C₁-C₆ alkyl optionally substitutedwith an imaging moiety, heteroaryl optionally substituted with animaging moiety, and an imaging moiety;

M is selected from the group consisting of hydrogen, alkoxyalkyloptionally substituted with an imaging moiety, alkyloxy optionallysubstituted with an imaging moiety, aryl optionally substituted with animaging moiety, C₁-C₆ alkyl optionally substituted with an imagingmoiety, heteroaryl optionally substituted with an imaging moiety, and animaging moiety; or

L and M, together with the atom to which they are attached, may form athree-, four-, five-, or six-membered carbocyclic ring;

Q is halo or haloalkyl;

n is 0, 1, 2, or 3;

R²¹, R²², R²⁷, and R²⁸ are independently selected from hydrogen, C₁-C₆alkyl optionally substituted with an imaging moiety, and an imagingmoiety;

R²³, R²⁴, R²⁵, and R²⁶ are independently selected from hydrogen,halogen, hydroxyl, alkyloxy, C₁-C₆ alkyl optionally substituted with animaging moiety, and an imaging moiety;

R²⁹ is C₁-C₆ alkyl optionally substituted with an imaging moiety; and

Y is selected from the group consisting of a bond, carbon, and oxygen;provided that when Y is a bond, K and L are absent, and M is selectedfrom the group consisting of aryl optionally substituted with an imagingmoiety and heteroaryl optionally substituted with an imaging moiety; andprovided that when Y is oxygen, K and L are absent, and M is selectedfrom hydrogen, alkoxyalkyl optionally substituted with an imagingmoiety, aryl optionally substituted with an imaging moiety, C₁-C₆ alkyloptionally substituted with an imaging moiety, and heteroaryl optionallysubstituted with an imaging moiety;

provided that at least one imaging moiety is present in the compound. Insome embodiments, the imaging moiety is ¹⁸F.

In some cases, J is selected from N(R²⁷), S, O, C(═O), C(═O)O,NHCH₂CH₂O, a bond, or C(═O)N(R²⁷). In some cases when present, K isselected from hydrogen, alkoxyalkyl optionally substituted with animaging moiety, alkyloxy optionally substituted with an imaging moiety,aryl optionally substituted with an imaging moiety, C₁-C₆ alkyloptionally substituted with an imaging moiety, heteroaryl optionallysubstituted with an imaging moiety, and an imaging moiety. In somecases, when present, L is selected from hydrogen, alkoxyalkyl optionallysubstituted with an imaging moiety, alkyloxy optionally substituted withan imaging moiety, aryl optionally substituted with an imaging moiety,C₁-C₆ alkyl optionally substituted with an imaging moiety, heteroaryloptionally substituted with an imaging moiety, and an imaging moiety. Insome cases, M is selected from hydrogen, alkoxyalkyl optionallysubstituted with an imaging moiety, alkyloxy optionally substituted withan imaging moiety, aryl optionally substituted with an imaging moiety,C₁-C₆ alkyl optionally substituted with an imaging moiety, heteroaryloptionally substituted with an imaging moiety, and an imaging moiety. Insome cases, L and M, together with the atom to which they are attached,form a three- or four-membered carbocyclic ring. In some cases Q is haloor haloalkyl. In some cases, n is 0, 1, 2, or 3. In some cases, R²¹,R²², R²³, R²⁴, R²⁵, R²⁶, and R²⁷ are independently selected fromhydrogen, C₁-C₆ alkyl optionally substituted with an imaging moiety, andan imaging moiety. In some cases R²⁹ is C₁-C₆ alkyl optionallysubstituted with an imaging moiety. In some cases, Y is selected from abond, carbon, and oxygen; provided that when Y is a bond, K and L areabsent and M is selected from aryl and heteroaryl; and provided thatwhen Y is oxygen, K and L are absent and M is selected from hydrogen,alkoxyalkyl optionally substituted with an imaging moiety, aryl, C₁-C₆alkyl optionally substituted with an imaging moiety, and heteroaryl.

In some cases, J is O. In some cases R²⁹ is methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, or t-butyl, each may be optionallysubstituted with an imaging moiety. In certain embodiment, R²⁹ ist-butyl. In some cases, Q is chloro. In some cases, all of R²¹, R²²,R²³, R²⁴, R²⁵, R²⁶, and R²⁷ are hydrogen. In some cases, Y is carbon, Kand L are hydrogen, and M is alkoxyalkyl optionally substituted with animaging moiety, alkyloxy optionally substituted with an imaging moiety,aryl optionally substituted with an imaging moiety, C₁-C₆ alkyloptionally substituted with an imaging moiety, heteroaryl optionallysubstituted with an imaging moiety, or an imaging moiety. In some cases,Y is carbon, K and L are hydrogen, and M is alkyloxy optionallysubstituted with an imaging moiety.

In some embodiments, an imaging agent for imaging perfusion comprisesthe formula:

wherein:

W is alkyl or heteroalkyl, optionally substituted;

R¹ is alkyl, optionally substituted;

R² is hydrogen or halide;

each R³ can be the same or different and is alkyl optionally substitutedwith an imaging moiety or heteroalkyl optionally substituted with animaging moiety; and

n is 1, 2, 3, 4, or 5.

In some embodiments, the imaging agent for imaging perfusion (e.g.,cardiac perfusion) comprises the structure:

or a pharmaceutically acceptable salt thereof, hereinafter referred toas “Imaging Agent-2.”

Those of ordinary skill in the art will be aware of other suitableimaging agents for imaging perfusion (e.g., cardiac perfusion). Forexample, suitable imaging agents for imaging perfusion include, but arenot limited to, thallium-201, technetium-99m sestamibi, technetium-99mtetrofosmin, rubidium-82 chloride, oxygen-15 water, and nitrogen-13ammonia. In some embodiments, an imaging agent for imaging perfusion isas described in International Patent Publication No. WO 2005/079391,published Sep. 1, 2005, to Casebier et al.; International PatentPublication No. WO 2005/105159, published Nov. 10, 2005, to Radeke etal., International Patent Publication No. WO 2011/097649, published Aug.11, 2011, to Cesati et al.; each of which is incorporated herein byreference.

G2. Innervation Imaging Agents

Some embodiments of the present invention comprise an imaging agent forimaging innervation (e.g., innervation of the heart). Those of ordinaryskill in the art will be aware of imaging agents which are capable ofimaging innervation.

In some embodiments, an imaging agent for imaging innervation may be anagent, which is used to monitor and/or assess certain aspects of thesympathetic nervous system (SNS). The SNS plays a role in normal cardiacregulation and/or the pathogenesis of heart failure development and/orprogression. Generally, following myocardial insult (e.g., myocardialinfarction, valve regurgitation, hypertension), compensatory activationof the SNS is induced to help maintain sufficient cardiac output.Sustained elevation of the cardiac SNS can cause elevated cardiacnorepinephrine (NE) release, down-regulation of the beta1 adrenergicreceptor, and/or down-regulation of the NE transporter (NET), which canresult in spillover of NE. Elevated levels of NE can be attributed tocardiac myocyte hypertrophy, fibroblast activation, collagen deposition,and/or myocyte apoptosis, which can result in ventricle remodelingand/or susceptibility to arrhythmia.

In some embodiments, the imaging agents for imaging innervation asdescribed herein may act as norepinephrine transporter ligands thattarget or bind NET. In some embodiments, the methods comprise detectingNET, including determining NET levels, in a subject, wherein thedetermining may comprise determining the level, density, function,and/or localization of NET in a subject or portion thereof. In certainembodiments, without wishing to be bound by a particular theory, theimaging agent binds to norepinephrine transporters (NET) allowing forimaging of innervation (e.g., cardiac sympathetic innervation) or NETactivity.

In some embodiments, agents for imaging cardiac innervation may beutilized in the assessment of heart failure. In certain embodiments, themethods comprise an assessment of heart failure progression in asubject, wherein the assessment may include determination of theeffectiveness of a treatment regimen. In some cases, the treatmentregimen may include a beta blocker. In other cases, the treatment mayrequire implantation of a pacemaker or implantablecardioverter-defibrillator (ICD). In certain embodiments, agents forimaging cardiac innervation may be useful in the prediction of a timecourse for heart failure disease progression.

In some aspects, global images (e.g., global NET images) are acquired,and in other aspects, regional images (e.g., regional NET images) areacquired following administration of an imaging agent that targets NET,wherein a global image is an image of all or substantially all of anorgan (e.g., heart, kidney, pancreas), and a regional image is an imageof only a portion of an organ. In some cases, changes in NET may be usedto assess cardiac sympathetic innervation and/or myocardial sympatheticfunction in a subject.

Utilizing an imaging agent that targets NET permits imaging of thelocation, concentration, density, and/or distribution of NETs and alsocan be used to detect changes in NET location, concentration, densityand/or distribution over time, for example, by acquiring a first NETimage in a subject or region of a subject; obtaining a subsequent NETimage of the subject or the region of the subject, and comparing thefirst and subsequent images. Differences between the images can provideinformation on the change in NET status in the subject or region of thesubject. Changes in a NET parameter (e.g., location, density,concentration, and/or distribution) over time may be assessed andcorrelated with disease onset, progression, and/or regression. In somecases, the detection comprises detection of the level (e.g.,concentration) of NET, detection of the density of NET, detection of NETfunction, and/or detection of the localization of NET.

In some embodiments, the imaging agent employed for imaging innervationcomprises the structure:

or a pharmaceutically acceptable salt thereof, hereinafter referred toas “Imaging Agent-1.” In some embodiments, Imaging Agent-1 is providedas a formate or ascorbate salt.

In some embodiments, a compound for imaging innervation is providedcomprising Formula (Ia):

R⁰—Ar-L-R¹  (Ia)

wherein

Ar is substituted or unsubstituted, monocyclic or bicyclic aryl; orsubstituted or unsubstituted, monocyclic or bicyclic heteroaryl;

L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene;substituted or unsubstituted, cyclic or acyclic alkenylene; substitutedor unsubstituted, cyclic or acyclic alkynylene; or substituted orunsubstituted, cyclic or acyclic heteroaliphatic;

R¹ is a substituted or unsubstituted nitrogen-containing moiety; and

R⁰ is halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A2))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂,—NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1),—NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1),—C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1),—OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂;

each occurrence of R^(A1) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; and

R⁰ or R¹ is substituted with an imaging moiety selected from the groupconsisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I, or is associated with animaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator, or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or a saltthereof.

In some embodiments, the agent for imaging innervation comprises acompound as described above in Section A entitled “Imaging Agents.” Insome embodiments, the agent for imaging innervation is of the formula:

or a pharmaceutically acceptable salt thereof.

Those of ordinary skill in the art will be aware of other suitableimaging agents for imaging innervation (e.g., cardiac innervation). Forexample, other suitable imaging agents for imaging innervation include,but are not limited to, ¹²³I-meta-iodobenzylguanidine (MIBG),¹¹C-meta-hydroxyephedrine (HED) and ¹¹C-epinephrine. See, for example,Bengel F M, Schwaiger M. Assessment of cardiac sympathetic neuronalfunction using PET imaging. J Nucl Cardiol. 2004; 11(5):603-16; HennemanM M, Bengel F M, van der Wall E E, Knuuti J, Bax J J. Cardiac neuronalimaging: application in the evaluation of cardiac disease. J NuclCardiol. 2008; 15(3):442-55; Travin M I. Cardiac neuronal imaging at theedge of clinical application. Cardiol Clin. 2009; 27(2):311-27; andCarrio I. Cardiac neurotransmission imaging. J Nucl Med. 2001; 42(7):1062-76, incorporated by reference herein. In some embodiments, animaging agent for imaging perfusion is as described in InternationalPatent Publication No. WO 2008/083056, published Jul. 10, 2008, toPurohit et al., incorporated herein by reference.

H. Exemplary Cassettes and Reaction Systems

In some embodiments, systems, methods, kits, and cassettes are providedfor the synthesis of an imaging agent as described herein. In someembodiments, an imaging agent may be prepared using an automatedreaction system comprising a disposable or single use cassette. Thecassette may comprise all the non-radioactive reagents, solvents,tubing, valves, reaction vessels, and other apparatus and/or componentsnecessary to carry out the preparation of a given batch of imagingagent. The cassette allows the reaction system to have the flexibilityto make a variety of different imaging agents with minimal risk ofcross-contamination, by simply changing the cassette. By the term“cassette” is meant a piece of apparatus designed to fit removably andinterchangeably onto automated reaction systems, in such a way thatmechanical movement of moving parts of the automated reaction systemcontrols the operation of the cassette from outside the cassette, i.e.,externally. In certain embodiments, a cassette comprises a lineararrangement of valves, each linked to a port where various reagents,cartridges, syringes, and/or vials can be attached, by either needlepuncture of a septum-sealed vial, or by gas-tight, marrying joints. Eachvalve may have a male-female joint which interfaces with a correspondingmoving arm of the automated synthesizer. External rotation of the armcan control the opening or closing of the valve when the cassette isattached to the automated reaction system. Additional moving parts ofthe automated reaction system are designed to clip onto syringe plungertips, and thus raise or depress syringe barrels. An automated reactionsystem may further include a controller and one or more controllablevalves in electrical communication with the controller. An automatedreaction system may also include additional vessels, valves, sensors,heaters, pressurizing elements, etc., in electrical communication withthe controller. An automated reaction system may be operated by acontroller using suitable software for control of valve openings andclosings, heating, cooling, pressure levels, fluid movement, flow rate,etc. The automated reaction system may optionally include a computeroperating system, software, controls, etc., or other component. Inaddition, the automated reaction system may comprise a mount for thecassette.

Examples of automated reaction systems (e.g., a nucleophilic reactionsystem), include, but are not limited to, the Explora GN or RN synthesissystem (Siemens Medical Solutions USA, Inc.), GE-Tracerlab-MX synthesissystem (GE Healthcare), Eckert & Zeigler Modular-Lab Synthesis system,etc., which are commonly available at PET manufacturing facilities.

I. Noise Filtering Optimization

The invention also relates, in part, to methods for optimizing noisefiltering parameters for PET myocardial imaging. The invention providesa methodology for obtaining optimal noise filtering parameters for any2D or 3D camera (or scanner as the terms are used interchangeably) usedto obtain PET images. The invention also provides optimal noisefiltering parameters to be applied to imaging data. These parameters maybe used in an imaging data algorithm which may be performed manually orelectronically (e.g., via software).

In accordance with the invention, it has been found that a cardiacphantom simulation using known patient myocardial standardized uptakevalues (SUVs) is an effective method to determine the optimal noisefilter parameter set that can produce high-quality diagnostic images.This has been exemplified, as described in the Examples, from the use ofimaging data obtained with PET myocardial perfusion Imaging Agent-2.

One method comprises obtaining 3D perfusion imaging data from a cardiacphantom having a defect, applying a series of smoothing filters to thedata, and selecting the filter that provides less than 5% defectcontrast degradation. The smoothing filter is typically a weightedGaussian function defined by full width half maximum (FWHM) values. Itwas found in accordance with the invention that a Gaussian filter set atFWHM of 8 mm was optimal for 3D myocardial perfusion images acquired atrest and after either pharmacological stress or exercise induced stress.As shown in Table B of Example 2, a filter set at FWHM of 8 mm achievesthe desired defect contrast degradation of less than 5% and a nearmaximal signal to noise ratio (SNR). At FWHM less than 8 mm the SNRdecreases for each of these data sets and at FWHM more than 8 mm thedefect contrast degradation is above the desired 5%. The cardiac phantommay have a defect of 45+/−15°, 45+/−10°, 45+/−5°, 45+/−1°, or simply45°.

Another method comprises obtaining 2D gated imaging data from a cardiacphantom having a defect, applying a series of smoothing filters to thedata, and selecting the filter that provides more than 90% leftventricular volume (LVV) accuracy. The smoothing filter is typically aweighted Gaussian function defined by FWHM values. It was found inaccordance with the invention that a Gaussian filter of FWHM of 15 mmwas optimal for 2D gated images acquired at rest, and a Gaussian filterof FWHM of 12 mm was optimal for 2D gated images acquired afterpharmacological and exercise-induced stress. As shown in Table B, afilter set at FWHM less than or greater than 15 mm achieved LVV accuracyranging from 50-78% as compared to the FWHM 15 mm filter which achieved93% LVV accuracy, for images obtained at rest. A filter set at FWHM of12 mm or 15 mm achieved LVV accuracies of about 93% and 91% for imagesobtained after pharmacological and exercise-induced stress, while FWHMless than 12 mm or greater than 15 mm achieved suboptimal LVV accuraciesranging from 65-84%.

Thus, the invention provides a method comprising obtaining 3D perfusionimages from a patient and applying to such images a FWHM of 8 mm. Theinvention also provides obtaining 2D gated images from a patient atrest, after pharmacological stress and after exercised-induced stressand applying to such images a FWHM of 15 mm, 12 or 15 mm, and 12 or 15mm, respectively.

It is to be understood that the foregoing methods can be used whenacquiring myocardial perfusion images using a variety of myocardialperfusion imaging agents as described herein. In important embodiments,the myocardial perfusion imaging agent includes ¹⁸F as an imagingmoiety, e.g., Imaging Agent-2.]

J. Pharmaceutical Compositions

The imaging agents described herein may be combined with one or morepharmaceutically acceptable excipients to form a pharmaceuticalcomposition that is suitable for administration to a subject, includinga human. As would be appreciated by one of skill in this art, theexcipients may be chosen, for example, based on the route ofadministration as described below, the imaging agent being delivered,time course of delivery of the agent, and/or the health/condition of thesubject. The pharmaceutical composition may be a solid or liquid.

Pharmaceutical compositions of the present invention and for use inaccordance with the present invention may include a pharmaceuticallyacceptable excipient or carrier. As used herein, the term“pharmaceutically acceptable excipient” or “pharmaceutically acceptablecarrier” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose, and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose, andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil; safflower oil; sesame oil; olive oil; corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; detergents such as Tween 80; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol;and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of theformulator.

Pharmaceutically acceptable excipients include any and all solvents,diluents or other liquid vehicles, dispersion or suspension aids,surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants and the like, as suitedto the particular dosage form desired. General considerations informulation and/or manufacture of pharmaceutical compositions agents canbe found, for example, in Remington's Pharmaceutical Sciences, SixteenthEdition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), andRemington: The Science and Practice of Pharmacy, 21st Edition(Lippincott Williams & Wilkins, 2005).

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include the steps of bringing the compound of the presentinvention (the “active ingredient”) into association with a carrierand/or one or more other accessory ingredients, and then, if necessaryand/or desirable, shaping and/or packaging the product into a desiredsingle- or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.As used herein, a “unit dose” is discrete amount of the pharmaceuticalcomposition comprising a predetermined amount of the active ingredient.The amount of the active ingredient is generally equal to the dosage ofthe active ingredient which would be administered to a subject and/or aconvenient fraction of such a dosage such as, for example, one-half orone-third of such a dosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition of the invention will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.By way of example, the composition may comprise between 0.1% and 100%(w/w) active ingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calciumphosphate, dicalcium phosphate, calcium sulfate, calcium hydrogenphosphate, sodium phosphate lactose, sucrose, cellulose,microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodiumchloride, dry starch, cornstarch, powdered sugar, and combinationsthereof.

Exemplary preservatives include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, alcoholpreservatives, acidic preservatives, and other preservatives.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfite, sodium iodide, sodiummetabisulfite, sodium nitrite, sodium sulfite, and sodium thiosulfate.

Exemplary chelating agents include ethylenediaminetetraacetic acid(EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodiumedetate, trisodium edetate, calcium disodium edetate, dipotassiumedetate, and the like), citric acid and salts and hydrates thereof(e.g., citric acid monohydrate), fumaric acid and salts and hydratesthereof, malic acid and salts and hydrates thereof, phosphoric acid andsalts and hydrates thereof, and tartaric acid and salts and hydratesthereof. Exemplary antimicrobial preservatives include benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butyl paraben, methylparaben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoicacid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol,phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate,and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylatedhydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS),sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus,Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, andEuxyl. In certain embodiments, the preservative is an anti-oxidant. Inother embodiments, the preservative is a chelating agent.

Exemplary buffering agents include citrate buffer solutions, acetatebuffer solutions, phosphate buffer solutions, ammonium chloride, calciumcarbonate, calcium chloride, calcium citrate, calcium glubionate,calcium gluceptate, calcium gluconate, D-gluconic acid, calciumglycerophosphate, calcium lactate, propanoic acid, calcium levulinate,pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasiccalcium phosphate, calcium hydroxide phosphate, potassium acetate,potassium chloride, potassium gluconate, potassium mixtures, dibasicpotassium phosphate, monobasic potassium phosphate, potassium phosphatemixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodiumcitrate, sodium lactate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline,Ringer's solution, ethyl alcohol, etc., and combinations thereof.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugates of theinvention are mixed with solubilizing agents such as Cremophor,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and combinations thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

Suitable devices for use in delivering intradermal pharmaceuticalcompositions described herein include short needle devices such as thosedescribed in U.S. Pat. Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288;4,270,537; 5,015,235; 5,141,496; and 5,417,662. Intradermal compositionscan be administered by devices which limit the effective penetrationlength of a needle into the skin, such as those described in PCTpublication WO 99/34850 and functional equivalents thereof. Jetinjection devices which deliver liquid vaccines to the dermis via aliquid jet injector and/or via a needle which pierces the stratumcorneum and produces a jet which reaches the dermis are suitable. Jetinjection devices are described, for example, in U.S. Pat. Nos.5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189;5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335;5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880;4,940,460; and PCT publications WO 97/37705 and WO 97/13537. Ballisticpowder/particle delivery devices which use compressed gas to acceleratevaccine in powder form through the outer layers of the skin to thedermis are suitable. Alternatively or additionally, conventionalsyringes can be used in the classical Mantoux method of intradermaladministration.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.

The pharmaceutical compositions of this invention can be administered tohumans and/or to other animals parenterally (e.g., by intravenous,intramuscular, subcutaneous, or intraperitoneal injection). The mode ofadministration will vary depending on the intended use, as is well knownin the art.

K. Kits

Systems, methods, kits, and/or cassettes are provided comprising animaging agent or an imaging agent precursor (or a first imaging agentand a second imaging agent) as described herein or a composition thereofand/or for preparation of an imaging agent. In some embodiments, a kitscomprises an imaging agent for imaging perfusion and an imaging agentfor imaging innervation (e.g., as described in Sections G1 and G2). Insome embodiments, kits for the administration of an imaging agent areprovided. In some cases, the composition provided with the kit may beused for or in the preparation of an imaging agent for detecting,imaging, and/or monitoring a disorder or condition. Kits of theinvention may include, for example, a container comprising an imagingagent or an imaging agent precursor and instructions for use. Kits maycomprise a sterile, non-pyrogenic, formulation comprising apredetermined amount of an imaging agent or an imaging agent precursor,and optionally other components. A container that may be used inconjunction with an imaging agent for example, to deliver and/oradminister the imaging agent to a subject, may be a syringe, bottle,vial, or tube. Instructions in a kit of the invention may relate tomethods for synthesizing an imaging agent or an imaging agent precursor,methods of diluting the imaging agent or the imaging agent precursor,methods of administering the imaging agent to a subject for diagnosticimaging, or other instructions for use. An imaging agent or an imagingagent precursor may be provided in a kit and additional preparationsbefore use may optionally include diluting the imaging agent or imagingagent precursor to a usable concentration.

In some cases, a kit can also include one or more vials containing adiluent for preparing an imaging agent composition for administration toa subject (e.g., a human). A diluent vial may contain a diluent such asphysiological saline or water for diluting the imaging agent. Forexample, the imaging agent may be packaged in a kit in a ready-to-injectformulation, or may require some reconstitution or dilution whereby afinal composition/formulation for injection or infusion is prepared.

Instructions in a kit of the invention may also include instructions foradministering the imaging agent to a subject and may include informationon dosing, timing, stress induction, etc. For example, a kit may includean imaging agent or imaging agent precursor as described herein alongwith instructions describing the intended application and the properadministration of the agent to a subject. As used herein, “instructions”can define a component of instruction and/or promotion, and typicallyinvolve written instructions on or associated with packaging of theinvention. Instructions also can include any oral or electronicinstructions provided in any manner such that a user will clearlyrecognize that the instructions are to be associated with the kit, forexample, audiovisual (e.g., videotape, DVD), internet, and/or web-basedcommunications. The written instructions may be in a form prescribed bya governmental agency regulating the manufacture, use or sale ofpharmaceuticals products, which instructions can also reflect approvalby the agency of manufacture, use; or sale for human administration. Insome cases, the instructions can include instructions for mixing aparticular amount of the diluent with a particular amount of aconcentrated solution of the imaging agent or a solid preparation of theimaging agent, whereby a final formulation for injection or infusion isprepared for example, such that the resulting solution is at a suitableconcentration for administration to a subject (e.g., at a concentrationas described herein). A kit may include a whole treatment regimen of theinventive compound.

The kit may contain any one or more of the components described hereinin one or more containers. As an example, in one embodiment, the kit mayinclude instructions for mixing one or more components of the kit and/orisolating and mixing a sample and applying to a subject. The kit mayinclude a container housing an agent described herein (e.g., an imagingagent precursor or an imaging agent). The agent may be in the form of aliquid, gel, or solid (e.g., powder). The agent may be preparedsterilely, packaged in a syringe, and shipped refrigerated.Alternatively it may be housed in a vial or other container for storage.A second container may have other agents prepared sterilely.Alternatively, the kit may include an agent premixed and shipped in asyringe, vial, tube, or other container. The kit may have one or more orall of the components required to administer the agents to a subject,such as a syringe or i.v. needle tubing and bag.

It also will be understood that containers containing the components ofa kit of the invention, whether the container is a bottle, a vial (e.g.,with a septum), an ampoule, an infusion bag, or the like, can includeadditional indicia such as conventional markings that change color whenthe preparation has been autoclaved or otherwise sterilized. A kit ofthe invention may further include other components, such as syringes,labels, vials, tubing, catheters, needles, ports, and the like. In someaspect of the invention, a kit may include a single syringe containingthe imaging agent of the invention sufficient for administration and insome aspects of the invention a kit may include more than one syringe.

Buffers useful in the preparation of imaging agents and kits include,for example, phosphate, citrate, sulfosalicylate, and acetate buffers. Amore complete list can be found in the United States Pharmacopoeia.Lyophilization aids useful in the preparation of imaging agents and kitsinclude, for example, mannitol, lactose, sorbitol, dextran, FICOLL®polymer, and polyvinylpyrrolidine (PVP). Stabilization aids useful inthe preparation of imaging agents and kits include, for example,ascorbic acid, cysteine, monothioglycerol, sodium bisulfite, sodiummetabisulfite, gentisic acid, and inositol. Solubilization aids usefulin the preparation of imaging agents and kits include, for example,ethanol, glycerin, polyethylene glycol, propylene glycol,polyoxyethylene sorbitan monooleate, sorbitan monooleate, polysorbates,poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) block copolymers(e.g., Pluronics®) and lecithin. In certain embodiments, thesolubilizing aids are polyethylene glycol, cyclodextrins, and Pluronics.Bacteriostats useful in the preparation of imaging agents and kitsinclude, for example, benzyl alcohol, benzalkonium chloride,chlorobutanol, and methyl, propyl, or butyl paraben.

L. Definitions

For convenience, certain terms employed in the specification, examples,and appended claims are listed here.

Definitions of specific functional groups and chemical terms aredescribed in more detail below. For purposes of this invention, thechemical elements are identified in accordance with the Periodic Tableof the Elements, CAS version, Handbook of Chemistry and Physics, 75^(th)Ed., inside cover, and specific functional groups are generally definedas described therein. Additionally, general principles of organicchemistry, as well as specific functional moieties and reactivity, aredescribed in Organic Chemistry, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, the entire contents of which are incorporatedherein by reference.

Certain compounds of the present invention may exist in particulargeometric or stereoisomeric forms. The present invention contemplatesall such compounds, including cis- and trans-isomers, R- andS-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemicmixtures thereof, and other mixtures thereof, as falling within thescope of the invention. Additional asymmetric carbon atoms may bepresent in a substituent such as an alkyl group. All such isomers, aswell as mixtures thereof, are intended to be included in this invention.

Isomeric mixtures containing any of a variety of isomer ratios may beutilized in accordance with the present invention. For example, whereonly two isomers are combined, mixtures containing 50:50, 60:40, 70:30,80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomer ratios areall contemplated by the present invention. Those of ordinary skill inthe art will readily appreciate that analogous ratios are contemplatedfor more complex isomer mixtures.

If, for instance, a particular enantiomer of a compound of the presentinvention is desired, it may be prepared by asymmetric synthesis, or byderivation with a chiral auxiliary, where the resulting diastereomericmixture is separated and the auxiliary group cleaved to provide the puredesired enantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

The term “aliphatic,” as used herein, includes both saturated andunsaturated, nonaromatic, straight chain (i.e., unbranched), branched,acyclic, and cyclic (i.e., carbocyclic) hydrocarbons, which areoptionally substituted with one or more functional groups. As will beappreciated by one of ordinary skill in the art, “aliphatic” is intendedherein to include, but is not limited to, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, as usedherein, the term “alkyl” includes straight, branched and cyclic alkylgroups. An analogous convention applies to other generic terms such as“alkenyl”, “alkynyl”, and the like. Furthermore, as used herein, theterms “alkyl”, “alkenyl”, “alkynyl”, and the like encompass bothsubstituted and unsubstituted groups. In certain embodiments, as usedherein, “aliphatic” is used to indicate those aliphatic groups (cyclic,acyclic, substituted, unsubstituted, branched or unbranched) having 1-20carbon atoms. Aliphatic group substituents include, but are not limitedto, any of the substituents described herein, that result in theformation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl,heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino,thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo,aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino,arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy,heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy,aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy,arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which mayor may not be further substituted).

As used herein, the term “alkyl” is given its ordinary meaning in theart and refers to the radical of saturated aliphatic groups, includingstraight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl(alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkylsubstituted alkyl groups. In some cases, the alkyl group may be a loweralkyl group, i.e., an alkyl group having 1 to 10 carbon atoms (e.g.,methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, ordecyl). In some embodiments, a straight chain or branched chain alkylmay have 30 or fewer carbon atoms in its backbone, and, in some cases,20 or fewer. In some embodiments, a straight chain or branched chainalkyl may have 12 or fewer carbon atoms in its backbone (e.g., C₁-C₁₂for straight chain, C₃-C₁₂ for branched chain), 6 or fewer, or 4 orfewer. Likewise, cycloalkyls may have from 3-10 carbon atoms in theirring structure, or 5, 6 or 7 carbons in the ring structure. Examples ofalkyl groups include, but are not limited to, methyl, ethyl, propyl,isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, cyclobutyl, hexyl, andcyclochexyl.

The term “alkylene” as used herein refers to a bivalent alkyl group. An“alkylene” group is a polymethylene group, i.e., —(CH₂)_(z)—, wherein zis a positive integer, e.g., from 1 to 20, from 1 to 10, from 1 to 6,from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substitutedalkylene chain is a polymethylene group in which one or more methylenehydrogen atoms are replaced with a substituent. Suitable substituentsinclude those described herein for a substituted aliphatic group.

Generally, the suffix “-ene” is used to describe a bivalent group. Thus,any of the terms defined herein can be modified with the suffix “-ene”to describe a bivalent version of that moiety. For example, a bivalentcarbocycle is “carbocyclylene”, a bivalent aryl ring is “arylene”, abivalent benzene ring is “phenylene”, a bivalent heterocycle is“heterocyclylene”, a bivalent heteroaryl ring is “heteroarylene”, abivalent alkyl chain is “alkylene”, a bivalent alkenyl chain is“alkenylene”, a bivalent alkynyl chain is “alkynylene”, a bivalentheteroalkyl chain is “heteroalkylene”, a bivalent heteroalkenyl chain is“heteroalkenylene”, a bivalent heteroalkynyl chain is“heteroalkynylene”, and so forth.

The terms “alkenyl” and “alkynyl” are given their ordinary meaning inthe art and refer to unsaturated aliphatic groups analogous in lengthand possible substitution to the alkyls described above, but thatcontain at least one double or triple bond respectively.

In certain embodiments, the alkyl, alkenyl and alkynyl groups employedin the invention contain 1-20 aliphatic carbon atoms. In certain otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in theinvention contain 1-10 aliphatic carbon atoms. In yet other embodiments,the alkyl, alkenyl, and alkynyl groups employed in the invention contain1-8 aliphatic carbon atoms. In still other embodiments, the alkyl,alkenyl, and alkynyl groups employed in the invention contain 1-6aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl,and alkynyl groups employed in the invention contain 1-4 carbon atoms.Illustrative aliphatic groups thus include, but are not limited to, forexample, methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl, sec-butyl,isobutyl, t-butyl, n-pentyl, sec-pentyl, isopentyl, t-pentyl, n-hexyl,sec-hexyl, moieties and the like, which again, may bear one or moresubstituents. Alkenyl groups include, but are not limited to, forexample, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and thelike. Representative alkynyl groups include, but are not limited to,ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.

The term “cycloalkyl,” as used herein, refers specifically to groupshaving three to ten, preferably three to seven carbon atoms. Suitablecycloalkyls include, but are not limited to cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the caseof other aliphatic, heteroaliphatic, or heterocyclic moieties, mayoptionally be substituted with substituents including, but not limitedto aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl;heteroarylalkyl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy;alkylthio; arylthio; heteroalkylthio; heteroarylthio; —F; —Cl; —Br; —I;—OH; —NO₂; —CN; —CF₃; —CH₂CF₃; —CHCl₂; —CH₂OH; —CH₂CH₂OH; —CH₂NH₂;—CH₂SO₂CH₃; —C(O)R_(x); —CO₂(R_(x)); —CON(R_(x))₂; —OC(O)R_(x);—OCO₂R_(x); —OCON(R_(x))₂; —N(R_(x))₂; —S(O)₂R_(x); —NR_(x)(CO)R_(x),wherein each occurrence of R_(x) independently includes, but is notlimited to, aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, orheteroarylalkyl, wherein any of the aliphatic, heteroaliphatic,arylalkyl, or heteroarylalkyl substituents described above and hereinmay be substituted or unsubstituted, branched or unbranched, cyclic oracyclic, and wherein any of the aryl or heteroaryl substituentsdescribed above and herein may be substituted or unsubstituted.Additional examples of generally applicable substitutents areillustrated by the specific embodiments shown in the Examples that aredescribed herein.

The term “heteroaliphatic,” as used herein, refers to an aliphaticmoiety, as defined herein, which includes both saturated andunsaturated, nonaromatic, straight chain (i.e., unbranched), branched,acyclic, cyclic (i.e., heterocyclic), or polycyclic hydrocarbons, whichare optionally substituted with one or more functional groups, and thatcontain one or more oxygen, sulfur, nitrogen, phosphorus, or siliconatoms, e.g., in place of carbon atoms. In certain embodiments,heteroaliphatic moieties are substituted by independent replacement ofone or more of the hydrogen atoms thereon with one or more substituents.As will be appreciated by one of ordinary skill in the art,“heteroaliphatic” is intended herein to include, but is not limited to,heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,heterocycloalkenyl, and heterocycloalkynyl moieties. Thus, the term“heteroaliphatic” includes the terms “heteroalkyl,” “heteroalkenyl”,“heteroalkynyl”, and the like. Furthermore, as used herein, the terms“heteroalkyl”, “heteroalkenyl”, “heteroalkynyl”, and the like encompassboth substituted and unsubstituted groups. In certain embodiments, asused herein, “heteroaliphatic” is used to indicate those heteroaliphaticgroups (cyclic, acyclic, substituted, unsubstituted, branched orunbranched) having 1-20 carbon atoms. Heteroaliphatic group substituentsinclude, but are not limited to, any of the substituents describedherein, that result in the formation of a stable moiety (e.g.,aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl,heteroaryl, acyl, sulfinyl, sulfonyl, oxo, imino, thiooxo, cyano,isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino,heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino,heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy,alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy,heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy,heteroarylthioxy, acyloxy, and the like, each of which may or may not befurther substituted).

The term “heteroalkyl” is given its ordinary meaning in the art andrefers to an alkyl group as described herein in which one or more carbonatoms is replaced by a heteroatom. Suitable heteroatoms include oxygen,sulfur, nitrogen, phosphorus, and the like. Examples of heteroalkylgroups include, but are not limited to, alkoxy, amino, thioester,poly(ethylene glycol), and alkyl-substituted amino.

The terms “heteroalkenyl” and “heteroalkynyl” are given their ordinarymeaning in the art and refer to unsaturated aliphatic groups analogousin length and possible substitution to the heteroalkyls described above,but that contain at least one double or triple bond respectively.

Some examples of substituents of the above-described aliphatic (andother) moieties of compounds of the invention include, but are notlimited to aliphatic; heteroaliphatic; aryl; heteroaryl; alkylaryl;alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy;alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; —OH;—NO₂; —CN; —CF₃; —CHF₂; —CH₂F; —CH₂CF₃; —CHCl₂; —CH₂OH; —CH₂CH₂OH;—CH₂NH₂; —CH₂SO₂CH₃; —C(O)R_(x); —CO₂(R_(x)); —CON(R_(x))₂; —OC(O)R_(x);—OCO₂R_(x); —OCON(R_(x))₂; —N(R_(x))₂; —S(O)₂R_(x); —NR_(x)(CO)R_(x)wherein each occurrence of R_(x) independently includes, but is notlimited to, aliphatic, alycyclic, heteroaliphatic, heterocyclic, aryl,heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic,heteroaliphatic, alkylaryl, or alkylheteroaryl substituents describedabove and herein may be substituted or unsubstituted, branched orunbranched, cyclic or acyclic, and wherein any of the aryl or heteroarylsubstituents described above and herein may be substituted orunsubstituted. Additional examples of generally applicable substituentsare illustrated by the specific embodiments shown in the Examples thatare described herein.

The term “aryl” is given its ordinary meaning in the art and refers toaromatic carbocyclic groups, optionally substituted, having a singlering (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple fusedrings in which at least one is aromatic (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl). That is,at least one ring may have a conjugated pi electron system, while other,adjoining rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, arylsand/or heterocyclyls. The aryl group may be optionally substituted, asdescribed herein. Substituents include, but are not limited to, any ofthe previously mentioned substitutents, i.e., the substituents recitedfor aliphatic moieties, or for other moieties as disclosed herein,resulting in the formation of a stable compound. In some cases, an arylgroup is a stable mono- or polycyclic unsaturated moiety havingpreferably 3-14 carbon atoms, each of which may be substituted orunsubstituted. “Carbocyclic aryl groups” refer to aryl groups whereinthe ring atoms on the aromatic ring are carbon atoms. Carbocyclic arylgroups include monocyclic carbocyclic aryl groups and polycyclic orfused compounds (e.g., two or more adjacent ring atoms are common to twoadjoining rings) such as naphthyl groups.

The terms “heteroaryl” is given its ordinary meaning in the art andrefers to aryl groups comprising at least one heteroatom as a ring atom.A “heteroaryl” is a stable heterocyclic or polyheterocyclic unsaturatedmoiety having preferably 3-14 carbon atoms, each of which may besubstituted or unsubstituted. Substituents include, but are not limitedto, any of the previously mentioned substitutents, i.e., thesubstituents recited for aliphatic moieties, or for other moieties asdisclosed herein, resulting in the formation of a stable compound. Insome cases, a heteroaryl is a cyclic aromatic radical having from fiveto ten ring atoms of which one ring atom is selected from S, O, and N;zero, one, or two ring atoms are additional heteroatoms independentlyselected from S, O, and N; and the remaining ring atoms are carbon, theradical being joined to the rest of the molecule via any of the ringatoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl,pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and thelike.

It will also be appreciated that aryl and heteroaryl moieties, asdefined herein may be attached via an alkyl or heteroalkyl moiety andthus also include -(alkyl)aryl, -(heteroalkyl)aryl,-(heteroalkyl)heteroaryl, and -(heteroalkyl)heteroaryl moieties. Thus,as used herein, the phrases “aryl or heteroaryl moieties” and “aryl,heteroaryl, -(alkyl)aryl, -(heteroalkyl)aryl, -(heteroalkyl)heteroaryl,and -(heteroalkyl)heteroaryl” are interchangeable. Substituents include,but are not limited to, any of the previously mentioned substituents,i.e., the substituents recited for aliphatic moieties, or for othermoieties as disclosed herein, resulting in the formation of a stablecompound.

It will be appreciated that aryl and heteroaryl groups (includingbicyclic aryl groups) can be unsubstituted or substituted, whereinsubstitution includes replacement of one or more of the hydrogen atomsthereon independently with any one or more of the following moietiesincluding, but not limited to: aliphatic; alicyclic; heteroaliphatic;heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl;heteroalkylaryl; alkylheteroaryl; heteroalkylheteroaryl; alkoxy;aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio;heteroalkylthio; heteroarylthio; F; Cl; Br; I; —OH; —NO₂; —CN; —CF₃;—CH₂F; —CHF₂; —CH₂CF₃; —CHCl₂; —CH₂OH; —CH₂CH₂OH; —CH₂NH₂; —CH₂SO₂CH₃;—C(O)R_(x); —CO₂(R_(x)); —CON(R_(x))₂; —OC(O)R_(x); —OCO₂R_(x);—OCON(R_(x))₂; —N(R_(x))₂; —S(O)R_(x); —S(O)₂R_(x); —NR_(x)(CO)R_(x)wherein each occurrence of R_(x) independently includes, but is notlimited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic,aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl,heteroalkylaryl or heteroalkylheteroaryl, wherein any of the aliphatic,alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroarylsubstituents described above and herein may be substituted orunsubstituted, branched or unbranched, saturated or unsaturated, andwherein any of the aromatic, heteroaromatic, aryl, heteroaryl,-(alkyl)aryl or -(alkyl)heteroaryl substituents described above andherein may be substituted or unsubstituted. Additionally, it will beappreciated, that any two adjacent groups taken together may represent a4, 5, 6, or 7-membered substituted or unsubstituted alicyclic orheterocyclic moiety. Additional examples of generally applicablesubstituents are illustrated by the specific embodiments describedherein.

The term “heterocycle” is given its ordinary meaning in the art andrefers to refer to cyclic groups containing at least one heteroatom as aring atom, in some cases, 1 to 3 heteroatoms as ring atoms, with theremainder of the ring atoms being carbon atoms. Suitable heteroatomsinclude oxygen, sulfur, nitrogen, phosphorus, and the like. In somecases, the heterocycle may be 3- to 10-membered ring structures or 3- to7-membered rings, whose ring structures include one to four heteroatoms.

The term “heterocycle” may include heteroaryl groups, saturatedheterocycles (e.g., cycloheteroalkyl) groups, or combinations thereof.The heterocycle may be a saturated molecule, or may comprise one or moredouble bonds. In some cases, the heterocycle is a nitrogen heterocycle,wherein at least one ring comprises at least one nitrogen ring atom. Theheterocycles may be fused to other rings to form a polycylicheterocycle. The heterocycle may also be fused to a spirocyclic group.In some cases, the heterocycle may be attached to a compound via anitrogen or a carbon atom in the ring.

Heterocycles include, for example, thiophene, benzothiophene,thianthrene, furan, tetrahydrofuran, pyran, isobenzofuran, chromene,xanthene, phenoxathiin, pyrrole, dihydropyrrole, pyrrolidine, imidazole,pyrazole, pyrazine, isothiazole, isoxazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,triazole, tetrazole, oxazole, isoxazole, thiazole, isothiazole,phenanthridine, acridine, pyrimidine, phenanthroline, phenazine,phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane,thiolane, oxazole, oxazine, piperidine, homopiperidine(hexamethyleneimine), piperazine (e.g., N-methyl piperazine),morpholine, lactones, lactams such as azetidinones and pyrrolidinones,sultams, sultones, other saturated and/or unsaturated derivativesthereof, and the like. The heterocyclic ring can be optionallysubstituted at one or more positions with such substituents as describedherein. In some cases, the heterocycle may be bonded to a compound via aheteroatom ring atom (e.g., nitrogen). In some cases, the heterocyclemay be bonded to a compound via a carbon ring atom. In some cases, theheterocycle is pyridine, imidazole, pyrazine, pyrimidine, pyridazine,acridine, acridin-9-amine, bipyridine, naphthyridine, quinoline,benzoquinoline, benzoisoquinoline, phenanthridine-1,9-diamine, or thelike.

The terms “halo” and “halogen” as used herein refer to an atom selectedfrom the group consisting of fluorine, chlorine, bromine, and iodine.

The term “haloalkyl” denotes an alkyl group, as defined above, havingone, two, or three halogen atoms attached thereto and is exemplified bysuch groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.

The term “amino,” as used herein, refers to a primary (—NH₂), secondary(—NHR_(x)), tertiary (—NR_(x)R_(y)), or quaternary (—N⁺R_(x)R_(y)R_(z))amine, where R_(x), R_(y), and R_(z) are independently an aliphatic,alicyclic, heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety, asdefined herein. Examples of amino groups include, but are not limitedto, methylamino, dimethylamino, ethylamino, diethylamino,methylethylamino, iso-propylamino, piperidino, trimethylamino, andpropylamino.

The term “alkyne” is given its ordinary meaning in the art and refers tobranched or unbranched unsaturated hydrocarbon groups containing atleast one triple bond. Non-limiting examples of alkynes includeacetylene, propyne, 1-butyne, 2-butyne, and the like. The alkyne groupmay be substituted and/or have one or more hydrogen atoms replaced witha functional group, such as a hydroxyl, halogen, alkoxy, and/or arylgroup.

The term “alkoxy” (or “alkyloxy”), or “thioalkyl” as used herein refersto an alkyl group, as previously defined, attached to the parentmolecular moiety through an oxygen atom or through a sulfur atom. Incertain embodiments, the alkyl group contains 1-20 aliphatic carbonatoms. In certain other embodiments, the alkyl group contains 1-10aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl,and alkynyl groups employed in the invention contain 1-8 aliphaticcarbon atoms. In still other embodiments, the alkyl group contains 1-6aliphatic carbon atoms. In yet other embodiments, the alkyl groupcontains 1-4 aliphatic carbon atoms. Examples of alkoxy, include but arenot limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy,t-butoxy, neopentoxy and n-hexoxy. Examples of thioalkyl include, butare not limited to, methylthio, ethylthio, propylthio, isopropylthio,n-butylthio, and the like.

The term “aryloxy” refers to the group, —O-aryl.

The term “acyloxy” refers to the group, —O-acyl.

The term “alkoxyalkyl” refers to an alkyl group substituted with atleast one alkoxy group (e.g., one, two, three, or more, alkoxy groups).For example, an alkoxyalkyl group may be —(C₁₋₆-alkyl)-O—(C₁₋₆-alkyl),optionally substituted. In some cases, the alkoxyalkyl group may beoptionally substituted with another alkyoxyalkyl group (e.g.,—(C₁₋₆-alkyl)-O—(C₁₋₆-alkyl)-O—(C₁₋₆-alkyl), optionally substituted.

It will be appreciated that the above groups and/or compounds, asdescribed herein, may be optionally substituted with any number ofsubstituents or functional moieties. That is, any of the above groupsmay be optionally substituted. As used herein, the term “substituted” iscontemplated to include all permissible substituents of organiccompounds, “permissible” being in the context of the chemical rules ofvalence known to those of ordinary skill in the art. In general, theterm “substituted” whether preceeded by the term “optionally” or not,and substituents contained in formulas of this invention, refer to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. When more than one position in any givenstructure may be substituted with more than one substituent selectedfrom a specified group, the substituent may be either the same ordifferent at every position. It will be understood that “substituted”also includes that the substitution results in a stable compound, e.g.,which does not spontaneously undergo transformation such as byrearrangement, cyclization, elimination, etc. In some cases,“substituted” may generally refer to replacement of a hydrogen with asubstituent as described herein. However, “substituted,” as used herein,does not encompass replacement and/or alteration of a key functionalgroup by which a molecule is identified, e.g., such that the“substituted” functional group becomes, through substitution, adifferent functional group. For example, a “substituted phenyl group”must still comprise the phenyl moiety and cannot be modified bysubstitution, in this definition, to become, e.g., a pyridine ring. In abroad aspect, the permissible substituents include acyclic and cyclic,branched and unbranched, carbocyclic and heterocyclic, aromatic andnonaromatic substituents of organic compounds. Illustrative substituentsinclude, for example, those described herein. The permissiblesubstituents can be one or more and the same or different forappropriate organic compounds. For purposes of this invention, theheteroatoms such as nitrogen may have hydrogen substituents and/or anypermissible substituents of organic compounds described herein whichsatisfy the valencies of the heteroatoms. Furthermore, this invention isnot intended to be limited in any manner by the permissible substituentsof organic compounds. Combinations of substituents and variablesenvisioned by this invention are preferably those that result in theformation of stable compounds useful for the formation of an imagingagent or an imaging agent precursor. The term “stable,” as used herein,preferably refers to compounds which possess stability sufficient toallow manufacture and which maintain the integrity of the compound for asufficient period of time to be detected and preferably for a sufficientperiod of time to be useful for the purposes detailed herein.

Examples of substituents include, but are not limited to, halogen,azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl,amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate,carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido,ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromaticmoieties, —CF₃, —CN, aryl, aryloxy, perhaloalkoxy, aralkoxy, heteroaryl,heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, amino, halide,alkylthio, oxo, acylalkyl, carboxy esters, -carboxamido, acyloxy,aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl,arylamino, aralkylamino, alkylsulfonyl, -carboxamidoalkylaryl,-carboxamidoaryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy-,aminocarboxamidoalkyl-, cyano, alkoxyalkyl, perhaloalkyl,arylalkyloxyalkyl, and the like. In some embodiments, a substituent mayalso be an imaging moiety (e.g., 18F) or a group for associating animaging moiety (e.g., a chelator).

Nitrogen-protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference. For example, nitrogen protectinggroups include, but are not limited to, carbamates (including methyl,ethyl and substituted ethyl carbamates (e.g. Troc), to name a few),amides, cyclic imide derivatives, N-alkyl and N-aryl amines, iminederivatives, and enamine derivatives, to name a few. In someembodiments, the nitrogen-protecting group is carbobenzyloxy (Cbz),p-methoxybenzyl carbonyl (MeOZ), t-butyloxycarbonyl (Boc),9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl(Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl(PMP), or p-toluenesulfonyloxy (Ts).

Nitrogen-protecting groups such as amide groups include, but are notlimited to, formamide, acetamide, chloroacetamide, trichloroacetamide,trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

Nitrogen-protecting groups such as carbamate groups include, but are notlimited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethylcarbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate,9-(2,7-dibromo)fluorenylmethyl carbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinylcarbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate(Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen-protecting groups such as sulfonamide groups include, but arenot limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr),2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen-protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

As used herein, the term “determining” generally refers to the analysisof a species or signal, for example, quantitatively or qualitatively,and/or the detection of the presence or absence of the species orsignals.

The term “diagnostic imaging,” as used herein, refers to a procedureused to detect an imaging agent.

The term “diagnosis” as used herein encompasses identification,confirmation, and/or characterization of a condition, a disease, and/ora disorder.

A “diagnostic kit” or “kit” comprises a collection of components, termedthe formulation, in one or more vials which are used by the practicingend user in a clinical or pharmacy setting to synthesize diagnosticradiopharmaceuticals. For example, the kit may be used by the practicingend user in a clinical or pharmacy setting to synthesize and/or usediagnostic radiopharmaceuticals. In some embodiments, the kit mayprovide all the requisite components to synthesize and use thediagnostic pharmaceutical except those that are commonly available tothe practicing end user, such as water or saline for injection and/orthe radioisotope (e.g., ¹⁸F). equipment for processing the kit duringthe synthesis and manipulation of the radiopharmaceutical, if required,equipment necessary for administering the radiopharmaceutical to thesubject such as syringes, shielding, imaging equipment, and the like. Insome embodiments, imaging agents may be provided to the end user intheir final form in a formulation contained typically in one vial orsyringe, as either a lyophilized solid or an aqueous solution.

As used herein, a “portion of a subject” refers to a particular regionof a subject, location of the subject. For example, a portion of asubject may be the brain, heart, vasculature, cardiac vessels, tumor,etc., of a subject.

As used herein a “session” of testing may be a single testing protocolthat a subject undergoes.

As used herein, the term “subject” refers to a human or non-human mammalor animal. Non-human mammals include livestock animals, companionanimals, laboratory animals, and non-human primates. Non-human subjectsalso specifically include, without limitation, horses, cows, pigs,goats, dogs, cats, mice, rats, guinea pigs, gerbils, hamsters, mink, andrabbits. In some embodiments of the invention, a subject is referred toas a “patient.” In some embodiments, a patient or subject may be underthe care of a physician or other health care worker, including, but notlimited to, someone who has consulted with, received advice from orreceived a prescription or other recommendation from a physician orother health care worker.

The term “perfusion” is given its ordinary meaning in the art and refersto the flow of blood to a muscle or a tissue. The term “cardiacperfusion” refers to the flow of blood to the heart. The term“innervation” is given its ordinary meaning in the art and refers to thesupply of nervous energy or of nerve stimulus sent to a portion of asubject. The term “cardiac innervation” refers to the supply of nervousenergy or of nerve stimulus sent to the heart of a subject.

Any of the compounds described herein may be in a variety of forms, suchas, but not limited to, salts, solvates, hydrates, tautomers, andisomers.

In certain embodiments, the imaging agent is a pharmaceuticallyacceptable salt of the imaging agent. The term “pharmaceuticallyacceptable salt” as used herein refers to those salts which are, withinthe scope of sound medical judgment, suitable for use in contact withthe tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like, and are commensurate with areasonable benefit/risk ratio. Pharmaceutically acceptable salts arewell known in the art. For example, Berge et al., describepharmaceutically acceptable salts in detail in J. PharmaceuticalSciences, 1977, 66, 1-19, incorporated herein by reference.Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from suitable inorganic and organic acids andbases. Examples of pharmaceutically acceptable, nontoxic acid additionsalts are salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄-alkyl)₄ salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counter ions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

In certain embodiments, the compound is in the form of a hydrate orsolvate. The term “hydrate” as used herein refers to a compoundnon-covalently associated with one or more molecules of water. Likewise,the term “solvate” refers to a compound non-covalently associated withone or more molecules of an organic solvent.

In certain embodiments, the compound described herein may exist invarious tautomeric forms. The term “tautomer” as used herein includestwo or more interconvertable compounds resulting from at least oneformal migration of a hydrogen atom and at least one change in valency(e.g., a single bond to a double bond, a triple bond to a single bond,or vice versa). The exact ratio of the tautomers depends on severalfactors, including temperature, solvent, and pH. Tautomerizations (i.e.,the reaction providing a tautomeric pair) may be catalyzed by acid orbase. Exemplary tautomerizations include keto-to-enol; amide-to-imide;lactam-to-lactim; enamine-to-imine; and enamine-to-(a different) enaminetautomerizations.

In certain embodiments, the compounds described herein may exist invarious isomeric forms. The term “isomer” as used herein includes anyand all geometric isomers and stereoisomers (e.g., enantiomers,diasteromers, etc.). For example, “isomer” includes cis- andtrans-isomers, E- and Z-isomers, R- and S-enantiomers, diastereomers,(D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixturesthereof, as falling within the scope of the invention. For instance, anisomer/enantiomer may, in some embodiments, be provided substantiallyfree of the corresponding enantiomer, and may also be referred to as“optically enriched.” “Optically-enriched,” as used herein, means thatthe compound is made up of a significantly greater proportion of oneenantiomer. In certain embodiments the compound of the present inventionis made up of at least about 90% by weight of a preferred enantiomer. Inother embodiments the compound is made up of at least about 95%, 98%, or99% by weight of a preferred enantiomer. Preferred enantiomers may beisolated from racemic mixtures by any method known to those skilled inthe art, including chiral high pressure liquid chromatography (HPLC) andthe formation and crystallization of chiral salts or prepared byasymmetric syntheses. See, for example, Jacques, et al., Enantiomers,Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen,S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistryof Carbon Compounds (McGraw-Hill, N Y, 1962); Wilen, S. H. Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972).

These and other aspects of the present invention will be furtherappreciated upon consideration of the following Examples, which areintended to illustrate certain particular embodiments of the inventionbut are not intended to limit its scope, as defined by the claims.

EXAMPLES

The following examples related to the compounds shown in FIG. 1 or saltsthereof. For example, Example 1 provides the synthesis of the compoundof Example 1 shown in FIG. 1.

Example 1 4-(4-(2-fluoroethoxy)phenyl)imidazolidin-2-imine

Part 1A—Preparation of tert-butyl[(Z)-[(tert-butoxycarbonyl)amino]{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}methylidene]carbamate

4-(2-Amino-1-hydroxyethyl)phenol hydrochloride (0.493 g, 2.6 mmol), wasdissolved in dry DMF (10.0 mL) then successively treated withN,N-diisopropylethylamine (645 μL, 3.6 mmol) andN,N′-di-Boc-1H-pyrazole-1-carboxamidine (1.15 g, 3.7 mmol), and theresulting solution stirred 1 h at ambient temperature. All volatileswere then removed in vacuo and the residue dissolved in EtOAc withtransfer to a separatory funnel. The EtOAc solution was exhaustivelywashed with dilute aqueous solutions of KHSO₄ and Na₂CO₃ then dried overNa₂SO₄, filtered and concentrated in vacuo. Purification bychromatography on silica using a step gradient from 7:3 hexanes/EtOAc to1:1 hexanes/EtOAc afforded the title compound as a white solid (0.837 g,2.12 mmol; 81.4%).

Part 1B—Preparation of tert-butyl[(Z)-[(tert-butoxycarbonyl)amino]({2-[4-(2-fluoroethoxy)phenyl]-2-hydroxyethyl}amino)methylidene]carbamate

The product of Part 1A (0.312 g, 0.790 mmol) was dissolved in dry DMSO(2.00 mL) then successively treated with K₂CO₃ (0.164 g, 1.19 mmol), KI(1.16 mg, 0.007 mmol) and 1-bromo-2-fluoroethane (89.0 μL, 1.19 mmol) atambient temperature. The resulting suspension was warmed to 50° C. andmaintained 3 h. After cooling to ambient temperature, the solution waspartitioned between EtOAc and H₂O (15 mL each) with transfer to aseparatory funnel. The layers separated and the EtOAc layer washed withsaturated aqueous NaCl, dried over Na₂SO₄, filtered and concentrated invacuo. Purification by chromatography on silica using 9:1 hexanes/EtOAcafforded the title compound as a white solid (0.178 g, 0.403 mmol;51.0%).

Part 1C—Preparation of 4-(4-(2-fluoroethoxy)phenyl)imidazolidin-2-imine,hydrochloric acid salt

The product of Part 1B (88.3 mg, 0.20 mmol) was dissolved in a solutionof Et₃SiH/H₂O/CF₃CO₂H (0.5:0.5/19 v/v/v; 2.0 mL) at ambient temperaturethen warmed to 55° C. and maintained 10 min. The resulting solution wascooled, concentrated in vacuo then directly purified by HPLC on aPhenomenex Luna C18 column (21.2×250 mm) using a 0.8%/min gradient from0-20% MeCN containing 0.1% HCO₂H and 10% H₂O at 20 mL/min. The mainproduct peak eluting at 17 min was collected, pooled then lyophilized toa hygroscopic white powder. The solids were re-dissolved in 0.5 N HCland lyophilized to afford the title compound as a white powder (14.2 mg,0.055 mmol; 27.3%).

Part 1D—Preparation of Preparation of [¹⁸F]Fluoride

[¹⁸F]Fluoride was produced by proton bombardment of [18O]H₂O in acyclotron; the nuclear chemical transformation is shown below and may besummarized as ¹⁸O(p,n)¹⁸F. For purposes of the bombardment, the chemicalform of the ¹⁸O is H₂ ¹⁸O. The chemical form of the resulting ¹⁸F isfluoride ion.

¹⁸O+proton→¹⁸F+neutron

According to established industry procedures, [¹⁸O]H₂O (2-3 mL) housedwithin a tantalum target body using Havar® foil, was bombarded with 11MeV protons (nominal energy); where the proton threshold energy for thereaction is 2.57 MeV and the energy of maximum cross section is 5 MeV.Target volume, bombardment time and proton energy each may be adjustedto manage the quantity of [¹⁸F]fluoride produced.

Part 1E—Preparation of 2-[¹⁸F]Fluoroethyl 4-Methylbenzenesulfonate

An MP1 anion exchange cartridge containing 1,000 mCi of [¹⁸F]NaF(produced according to the general procedure described in Part 1D) waseluted with 0.20% aqueous K₂CO₃ (1.0 mL), using an automated liquidhandling system, into a 25 mL conical-bottomed silanized flask. Allvolatiles were removed by applying a gentle stream of warm Ar andapplied vacuum. The contents of the flask were reconstituted with 0.5 mLof MeCN, and concentrated again using warm Ar and applied vacuum(azeotropic evaporation). A separate 5 mL conical-bottomed Wheaton™ vialwas used to prepared a solution of4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (22.5 mg) andethylene di-(p-toluenesulfonate) (3.8 mg) in MeCN (1.0 mL). Theconstituents of the vial were transferred to the 25 mL flask containing[¹⁸F]KF then positioned inside a microwave cavity (model 520 ResonanceInstruments, Skokie, Ill.) and irradiated for 3 min at 75 watts. Aftercooling, the contents of the microwave reaction vial were filteredthrough an anion exchange resin to remove residual fluoride ion,collected in a 5 mL conical-bottomed Wheaton™ reaction vial and usedwithout further purification in the subsequent reaction.

Part 1F—Preparation of4-{4-[2-(¹⁸F)fluoroethoxy]phenyl}imidazolidin-2-imine, formic acid salt

The product of Part 1E was transferred to a 5 mL conical-bottomedWheaton™ reaction vial containing the product of Part 1A (4.0 mg), K₂CO₃(10.9 mg) and anhydrous DMSO (400 μL). The resulting mixture was heatedat 80° C. for 30 min then cooled to ambient temperature then transferredto a clean 25 mL pear-shaped flask and diluted with H₂O (18.5 mL). Thecontents of the pear shaped flask were passed through a Sep Pak™ C18cartridge and the cartridge was rinsed with H₂O (5.0 mL). The desiredproduct was eluted from the cartridge with MeCN (3.0 mL) into a 5 mLconical-bottomed Wheaton™ vial. All volatiles were removed, and theresidue treated with a solution of trifluoroacetic acid in CH₂Cl₂ (1:1v/v, 2.0 mL). The resulting solution was warmed to 50° C., maintained 15min then cooled to ambient temperature and concentrated to dryness.Purification by HPLC on a Phenomenex Luna C18(2) column (10×250 mm, 5micron particle size, 100 Angstrom pore size) using a 5.0%/min gradientof 0-100% MeCN containing 0.1% HCO₂H acid at a flow rate of 2.0 mL/min.The title compound was collected, all volatiles removed, and the residuereconstituted with 10% aqueous ethanol solution for biologicalexperiments.

Example 2 4-(3-bromo-4-(2-fluoroethoxy)phenyl)imidazolidin-2-imine,hydrochloric acid salt

Part 2A—Preparation of tert-butyl[(Z)-[(tert-butoxycarbonyl)amino]{[2-hydroxy-2-(3-bromo-4-hydroxyphenyl)ethyl]amino}methylidene]carbamate

The product of Part 1A (1.75 g, 4.43 mmol), was dissolved H₂O/MeCN (3:2v/v, 75.0 mL) then successively treated with NaBrO₃ (0.735 g, 4.87 mmol)and NaHSO₃ (0.507 g, 4.87 mmol) and the resulting solution stirred 40min at ambient temperature. Additional NaBrO₃ (1.13 g, 7.5 mmol) andNaHSO₃ (0.780 g, 7.5 mmol) and the resulting solution stirred 3 h.Excess NaBrO₃ was then consumed by the addition of Na₂S₂O₃ (2.1 g, 13.3mmol). After 30 min, the MeCN was removed in vacuo and the aqueoussolution washed with CH₂Cl₂. The CH₂Cl₂ was further washed withsaturated aqueous NaCl, then dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica using a hexanes/EtOAc gradient to afford the title compound as awhite solid (0.635 g, 1.34 mmol; 30.2%).

Part 2B—Preparation of tert-butyl[(Z)-[(tert-butoxycarbonyl)amino]({2-[3-bromo-4-(2-fluoroethoxy)phenyl]-2-hydroxyethyl}amino)methylidene]carbamate

The product of Part 2A (0.306 g, 0.645 mmol) was dissolved in dry DMSO(3.00 mL) then successively treated with K₂CO₃ (0.134 g, 0.968 mmol), KI(single crystal) and 1-bromo-2-fluoroethane (48 μL, 0.645 mmol) atambient temperature. The resulting suspension was warmed to 50° C. andmaintained 1.5 h. After cooling to ambient temperature, the solution waspartitioned between EtOAc and H₂O with transfer to a separatory funnel.The layers separated and the EtOAc layer washed with H₂O followed bysaturated aqueous NaCl then dried over Na₂SO₄, filtered and concentratedin vacuo. Purification by chromatography on silica using a hexanes/EtOAcgradient afforded the title compound as a white solid (0.218 g, 0.419mmol; 64.9%).

Part 2C—Preparation of4-(3-bromo-4-(2-fluoroethoxy)phenyl)imidazolidin-2-imine, hydrochloricacid salt

The product of Part 2B (90.0 mg, 0.173 mmol) was dissolved in aqueousCF₃CO₂H (1:40 v/v; 2.0 mL) at ambient temperature then warmed to 55° C.and maintained 15 min. The resulting solution was cooled, concentratedin vacuo then directly purified by HPLC on a Phenomenex Luna C18 column(21.2×250 mm) using a 0.6%/min gradient from 5-23% MeCN containing 0.1%HCO₂H and 10% H₂O at 20 mL/min. The main product peak eluting at 2 minwas collected, pooled then lyophilized to a hygroscopic white powder.The solids were re-dissolved in 0.5 N HCl and lyophilized to afford thetitle compound as a white powder (18.6 mg, 0.055 mmol; 31.7%).

Part 2D—Preparation of4-{4-[2-(¹⁸F)fluoroethoxy]phenyl}imidazolidin-2-imine, formic acid salt

The product of Part 1E was transferred to a 5 mL conical-bottomedWheaton™ reaction vial containing the product of Part 2A (4.0 mg), K₂CO₃(10.9 mg) and anhydrous DMSO (400 μL). The resulting mixture was heatedat 80° C. for 30 min then cooled to ambient temperature then transferredto a clean 25 mL pear-shaped flask and diluted with H₂O (18.5 mL). Thecontents of the pear shaped flask were passed through a Sep Pak™ C18cartridge and the cartridge was rinsed with H₂O (5.0 mL). The desiredproduct was eluted from the cartridge with MeCN (3.0 mL) into a 5 mLconical-bottomed Wheaton™ vial. All volatiles were removed, and theresidue treated with a solution of trifluoroacetic acid in CH₂Cl₂ (1:1v/v, 2.0 mL). The resulting solution was warmed to 50° C., maintained 15min then cooled to ambient temperature and concentrated to dryness.Purification by HPLC on a Phenomenex Luna C18(2) column (10×250 mm, 5micron particle size, 100 Angstrom pore size) using a 5.0%/min gradientof 0-100% EtOH containing 0.1% HCO₂H acid at a flow rate of 2.0 mL/min.The title compound was collected, all volatiles removed, and the residuereconstituted with 10% aqueous ethanol solution for biologicalexperiments.

Example 3 1-(3-bromo-4-(fluoromethyl)benzyl)guanidine

Part 3A—Preparation of 3-bromo-4-(dibromomethyl)benzonitrile

A solution of 3-bromo-4-methyl-benzonitrile (5.00 g, 25.5 mmol) wasdissolved in CCl₄ (170 mL) and successively treated with NBS (18.2 g,102 mmol) and benzoyl peroxide (0618 g, 2.55 mmol) at ambienttemperature. The resulting solution was warmed to reflux, maintained 48h then cooled to ambient temperature and filtered through a scinteredglass funnel of medium porosity. The filtrate was concentrated, and thecrude orange solid thus obtained purified by chromatography on silicausing 49:1 hexanes/EtOAc to afford the title compound as a white solid(8.80 g, 24.9 mmol; 97.5%).

Part 3B—Preparation of 3-bromo-4-formylbenzonitrile

A solution of the product of Part 3A (8.80 g, 24.9 mmol) was dissolvedin wet DMSO (83 mL) at ambient temperature then warmed to 120° C. andmaintained 6 h. After cooling to ambient temperature, the resultingsolution was diluted with H₂O with transfer to a separatory funnel thenwashed EtOAc. The EtOAc solution was separated, washed with H₂O andsaturated aqueous NaCl then dried over Na₂SO₄, filtered and concentratedin vacuo to a yellow solid. Subsequent purification by chromatography onsilica using 20:1 hexanes/EtOAc afforded the title compound as a whitesolid (3.10 g, 14.8 mmol; 59.3%).

Part 3C—Preparation of 3-bromo-4-(hydroxymethyl)benzonitrile

A solution of the product of Part 3B (3.10 g, 14.7 mmol) was dissolvedMeOH (74 mL) at ambient temperature then cooled to 0° C. using an icebath. NaBH₄ (0.279 g, 7.38 mmol) was then added in one portion and theresulting solution maintained 40 min at 0° C. Dilute aqueous HCl wasadded to consume excess NaBH₄ then all volatiles removed in vacuo. Theresidue was redissolved in EtOAc with transfer to a separatory funnel,successively washed with 5% aqueous citric acid and H₂O, then dried overNa₂SO₄, filtered and concentrated in vacuo. Purification bychromatography on silica using a step gradient from 9:1 hexanes/EtOAc to1:1 hexanes/EtOAc afforded the title compound as a white solid (1.90 g,8.96 mmol; 60.7%).

Part 3D—Preparation of [4-(aminomethyl)-2-bromophenyl]methanol

LiAlH₄ (34.0 mmol; 34.0 mL of a 1.0 M solution in THF) was cooled to 0°C. using an ice bath then treated with MeOH (102 mmol; 26.4 mL of a 3.86M solution in THF) dropwise over 5 min. The product of Part 3C (0.900 g,4.24 mmol) was then added and the resulting solution warmed slowly toambient temperature as the ice bath melted. After 16 h total reactiontime, the solution was diluted with H₂O (9.0 mL) and the resultingsuspension filtered through a scintered glass funnel of medium porosity.The solids were exhaustively washed with H₂O and Et₂O then transferredto a separatory funnel and split. The aqueous layer was further washedwith Et₂O and EtOAc and the combined organic layers dried over Na₂SO₄,filtered and concentrated in vacuo to a yellow solid (0.591 g), whichwas used without further purification in the subsequent reaction.

Part 3E—Preparation of tert-but-2-yl[(Z)-{[3-bromo-4-(hydroxymethyl)benzyl]-amino}{[(tert-but-2-yloxy)carbonyl]amino}methylidene]carbamate

A solution of the product of Part 3D (0.585 g, 2.71 mmol) was dissolvedMeCN (9.00 mL) at ambient temperature then treated withN,N′-di-Boc-1H-pyrazole-1-carboxamidine (1.00 g, 3.25 mmol) in oneportion at ambient temperature. After 30 min, all volatiles were removedin vacuo and the residue purified by chromatography on silica using 5:1hexanes/EtOAc to afford the title compound as a white foam (0.860 g,1.88 mmol; 69.2%).

Part 3F—Preparation of 1-[3-bromo-4-(fluoromethyl)benzyl]guanidine,trifluoroacetic acid salt

Deoxo-Fluor® (0.240 mmol; 103 μL of a 50% solution in THF) was dilutedwith CH₂Cl₂ (137 μL) then cooled to −78° C. and treated with a solutionof the product of Part 3E (0.218 mmol; 218 μL of a 1.0 M solution inCH₂Cl₂) dropwise over 5 min. After 2 h, additional Deoxo-Fluor® (0.044mmol; 19 μL) was added, the resulting solution stirred 1 h at −78° C.then treated with saturated aqueous NaHCO₃ (273 μL) before warming toambient temperature. The layers were then separated and the aqueouslayer washed with CH₂Cl₂ (2×164 μL). The combined organic layers weredried over Na₂SO₄, filtered, concentrated in vacuo then redissolved indioxane (200 μL) and treated with concentrated HCl (600 μL) at ambienttemperature. After 1 h, all volatiles were removed and the residuepurified by HPLC on a Phenomenex Luna C18 column (21.2×250 mm) using a2%/min gradient from 0-60% MeCN containing 0.1% CF₃CO₂H and 10% H₂O at20 mL/min. The main product peak was collected, pooled and lyophilizedto a white solid (14 mg, 37 mmol; 17%).

Part 3G—Preparation of tert-but-2-yl[(Z)-[[3-bromo-4-(bromomethyl)benzyl]-amino]{[(tert-but-2-yloxy)carbonyl]amino}methylidene]carbamate

A solution of the product of Part 3E (75.0 mg, 0.164 mmol) was dissolveddry CH₂Cl₂ (2.00 mL) then successively treated with CBr₄ (109 mg, 0.327mmol) and PPh₃ (85.8 mg, 0.327 mmol) at ambient temperature; within 2 h,complete conversion to the expected product was observed. All volatileswere then removed in vacuo and the residue purified by chromatography onsilica using hexanes/EtOAc to afford the title compound as a white solidthat was used without further purification in the subsequentfluorination reaction.

Part 3H—Preparation of 1-{3-bromo-4-[[F]fluoromethyl]benzyl}guanidine,formic acid salt

An MP1 anion exchange cartridge containing 1,000 mCi of [¹⁸F]NaF(produced according to the general procedure described in Part 1D) waseluted with 0.20% aqueous K₂CO₃ (1.0 mL), using an automated liquidhandling system, into a 25 mL conical-bottomed silanized flask. Allvolatiles were removed by applying a gentle stream of warm Ar andapplied vacuum. The contents of the flask were reconstituted with 0.5 mLof MeCN, and concentrated again using warm Ar and applied vacuum(azeotropic evaporation). The residue was treated with a solution of4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (19.7 mg) inMeCN (0.90 mL) then transferred to a solution of the product of Part 3G(3.8 mg) in dry MeCN (0.40 mL). The resulting solution was heated to 49°C., maintained 45 min then cooled to ambient temperature andconcentrated. The residue thus obtained was redissolved in CH₂Cl₂ (0.40mL) then treated with CF₃CO₂H (1.00 mL) at ambient temperature. After 30min, all volatiles were removed and the residue purified by HPLC on aPhenomenex Luna C18(2) column (250×10 mm, 5 micron particle size, 100Angstrom pore size) using a 5.0%/min gradient of 0-100% MeCN containing0.1% HCO₂H acid at a flow rate of 2.0 mL/min. The title compound wascollected, all volatiles removed, and the residue reconstituted with 10%aqueous ethanol solution for biological experiments.

Example 4 1-(3-bromo-4-((2-fluoroethoxy)methyl)benzyl)guanidine

Part 4A—Preparation of1-{3-bromo-4-[(2-fluoroethoxy)methyl]benzyl}guanidine, trifluoroaceticacid salt

The product of Part 3E (0.100 g, 0.218 mmol) was dissolved in wet DMSO(2.20 mL) then treated with powdered NaOH (17.0 mg, 0.436 mmol) atambient temperature. After 30 min, 2-fluoroethyl4-methylbenzenesulfonate (48.0 mg, 0.218 mmol) was added in one portionand the resulting solution warmed to 75° C. and maintained 80 min. Aftercooling to ambient temperature, the solution was diluted with H₂O, withtransfer to a separatory funnel then exhaustively washed with EtOAc. Thecombined EtOAc washes were further washed with 5% aqueous citric acidthen dried over Na2SO4, filtered and concentrated in vacuo. The cruderesidue was redissolved in dioxane (200 μL) then treated withconcentrated HCl (600 μL) at ambient temperature. After 1 h, allvolatiles were removed and the residue purified by HPLC on a PhenomenexLuna C18 column (21.2×250 mm) using a 2%/min gradient from 0-30% MeCNcontaining 0.1% CF₃CO₂H and 10% H₂O at 20 mL/min. The main product peakwas collected, pooled and lyophilized to a white solid (10.7 mg, 25.6μmol; 11.7%).

Part 4B—Preparation of1-{3-bromo-4-[(2-[¹⁸F]fluoroethoxy)methyl]benzyl}guanidine,trifluoroacetic acid salt

The product of Part 1E was transferred to a 5 mL conical-bottomedWheaton™ reaction vial containing the product of Part 3E (4.0 mg), KOH(1.6 mg) and anhydrous DMSO (400 μL). The resulting mixture was heatedat 80° C. for 45 min, cooled to ambient temperature, concentrated invacuo then treated with CF₃CO₂H (1.00 mL) and warmed to 50° C. After 15min, the resulting mixture was cooled to ambient temperature,concentrated to dryness then purified by HPLC on a Phenomenex LunaC18(2) column (10×250 mm, 5 micron particle size, 100 Angstrom poresize) using a 5.0%/min gradient of 0-100% MeCN containing 0.1% HCO₂Hacid at a flow rate of 2.0 mL/min. The title compound was collected, allvolatiles removed, and the residue reconstituted with 10% aqueousethanol solution for biological experiments.

Example 5 1-[4-(2-fluoroethyl)benzyl]guanidine

Part 5A—Preparation of 4-(2-fluoroethyl)benzonitrile

Deoxo-Fluor® (0.843 g, 3.81 mmol) was dissolved in CH₂Cl₂ (0.50 mL) thencooled to −78° C. and treated with a solution of4-(2-hydroxyethyl)benzonitrile (3.47 mmol; 1.50 mL of a 2.31 M solutionin CH₂Cl₂) dropwise over 5 min. The resulting mixture warmed slowly toambient temperature as the cooling bath evaporated overnight. Saturatedaqueous NaHCO₃ (50 mL) was then added with transfer to a separatoryfunnel and the layers separated. The aqueous layer washed with CH₂Cl₂(3×25 mL) and the combined organic layers dried over MgSO₄, filtered andconcentrated in vacuo. Subsequent purification by chromatography onsilica using 4:1 hexanes/EtOAc afforded the title compound as a paleyellow oil (0.305 g, 2.04 mmol; 59.0%).

Part 5B—Preparation of 1-[4-(2-fluoroethyl)phenyl]methanamine

The product of Part 5A (0.210 g, 1.41 mmol) was dissolved in MeOH (13.0mL) then successively treated with concentrated HCl (1.00 mL) and Pd/C(0.141 mmol; 10 mol %) at ambient temperature. The headspace of thereaction vessel was sparged with 1 atm H₂ then maintained 2 h. Uponcomplete reduction, the headspace was sparged with dry N₂ and thecatalyst removed by filtration through Celite. The filter cake wasexhaustively washed with MeOH and the combined filtrates concentrated invacuo to a white powder. The crude material was used without furtherpurification in the subsequent reaction.

Part 5C—Preparation of 4-(2-fluoroethyl)benzylguanidine, trifluoroaceticacid salt

The product of Part 5B (0.150 g, 0.791 mmol) was dissolved in MeCN (4.00mL) and successively treated with N,N-diisopropylethylamine (152 mL,0.867 mmol) and 1H-pyrazole-1-carboximidamide (0.128 g, 0.870 mmol) atambient temperature. After 1 h, all volatiles were removed in vacuo andthe residue purified by HPLC on a Phenomenex Luna C18 column (21.2×250mm) using 1%/min gradient from 2-32% MeCN containing 0.1% CF₃CO₂H and10% H₂O at 20 mL/min. The main product peak was collected, pooled andlyophilized to a white solid (0.189 g, 0.484 mmol; 61.2%).

Part 5D—Preparation of 2-[4-(aminomethyl)phenyl]ethanol

4-(2-Hydroxyethyl)benzonitrile (0.402 g, 2.73 mmol) was dissolved inMeOH (10.0 mL) then successively treated with concentrated HCl (0.50 mL)and Pd/C (0.145 mmol; 5 mol %) at ambient temperature. The headspace ofthe reaction vessel was sparged with 1 atm H₂ then maintained 16 h. Uponcomplete reduction, the headspace was sparged with dry N₂ and thecatalyst removed by filtration through Celite. The filter cake wasexhaustively washed with MeOH and the combined filtrates concentrated invacuo to a white powder. The crude material was used without furtherpurification in the subsequent reaction.

Part 5E—Preparation of tert-butyl[(Z)-[(tert-butoxycarbonyl)amino]{[4-(2-hydroxyethyl)benzyl]amino}methylidenecarbamate

The product of Part 5D (0.553 g, 2.95 mmol) was dissolved in MeCN (5.00mL) and successively treated with N,N-diisopropylethylamine (513 μL,2.95 mmol) and N,N′-di-Boc-1H-pyrazole-1-carboxamidine (0.915 g, 2.95mmol) at ambient temperature. After 2 h, all volatiles were removed invacuo and the residue redissolved in CH₂Cl₂ (15 mL) with transfer to aseparatory funnel. The CH₂C12 solution was successively washed with 10%aqueous citric acid, H₂O and saturated aqueous NaCl (1×15 mL each) thendried over Na₂SO₄, filtered and concentrated in vacuo. Subsequentpurification by chromatography on silica, using a hexanes/EtOAc gradientfrom 0-100% EtOAc over 17 min, afforded the title compound as a whitesolid (0.777 g, 1.97 mmol; 67.0%).

Part 5F—Preparation of2-{4-[(N′,N″-bis(tert-butoxycarbonyl)carbamimidamido)methyl]-phenyl}ethyl4-methylbenzenesulfonate

The product of Part 5E (0.363 g, 0.918 mmol) was dissolved in CH₂Cl₂(4.00 mL) and successively treated with p-toluenesulfonyl chloride(0.264 g, 1.38 mmol) and pyridine (164 μL, 2.03 mmol) at 0° C. After 16h, the resulting solution was diluted with CH₂Cl₂ (10 mL) with transferto a separatory funnel. The CH₂Cl₂ solution was successively washed with5% aqueous NaHCO₃, H₂O and saturated aqueous NaCl (1×15 mL each) thendried over Na₂SO₄, filtered and concentrated in vacuo. Subsequentpurification by chromatography on silica, using a hexanes/EtOAc gradientfrom 0-100% EtOAc over 17 min, afforded the title compound as a whitesolid (0.393 g, 0.717 mmol; 77.8%).

Part 5G—Preparation of 1-{4-[2-[¹⁸F]fluoroethyl]benzyl}guanidine, formicacid salt

An MP1 anion exchange cartridge containing 1,000 mCi of [¹⁸F]NaF(produced according to the general procedure described in Part 1D) waseluted with 0.20% aqueous K₂CO₃ (1.0 mL), using an automated liquidhandling system, into a 25 mL conical-bottomed silanized flask. Allvolatiles were removed by applying a gentle stream of warm Ar andapplied vacuum. The contents of the flask were reconstituted with 0.5 mLof MeCN, and concentrated again using warm Ar and applied vacuum(azeotropic evaporation). The residue was treated with a solution of4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (20.5 mg) inMeCN (0.90 mL) then transferred to a solution of the product of Part 5F(3.97 mg) in dry MeCN (0.40 mL). The resulting solution was heated to60° C., maintained 45 min then cooled to ambient temperature andconcentrated. The residue thus obtained was redissolved in CF₃CO₂H (1.00mL), stirred 15 min at 4o ° C. then cooled and concentrated. Subsequentpurification by HPLC on a Phenomenex Luna C18(2) column (250×10 mm, 5micron particle size, 100 Angstrom pore size) using a 5.0%/min gradientof 0-100% MeCN containing 0.1% HCO₂H acid at a flow rate of 2.0 mL/min.The title compound was collected, all volatiles removed, and the residuereconstituted with 10% aqueous ethanol solution for biologicalexperiments.

Example 8 1-(3-bromo-4-(2-fluoroethyl)benzyl)guanidine

Part 8A—Preparation of 3-bromo-4-(2-hydroxyethyl)benzonitrile

4-(2-Hydroxyethyl)benzonitrile (1.22 g, 8.29 mmol) was dissolved inH₂O/H₂SO₄ (1:1 v/v, 8.00 mL) then treated with NBS (1.48 g, 8.32 mmol)in one portion at ambient temperature. The reaction vessel was thencovered with aluminum foil and maintained 48 h. The resulting solutionwas transferred to a separatory funnel, neutralized with 10% aqueousNaOH then washed with EtOAc (3×20 mL). The combined EtOAc washes weredried over Na₂SO₄, filtered and concentrated in vacuo. Subsequentpurification by chromatography on silica using 3:1 hexanes/EtOAcafforded the title compound as a pale yellow oil (0.285 g, 1.26 mmol;15.2%).

Part 8B—Preparation of 3-bromo-4-(2-fluoroethyl)benzonitrile

Deoxo-Fluor® (0.291 g, 1.32 mmol) was dissolved in CH₂Cl₂ (2.00 mL) thencooled to −78° C. and treated with a solution of the product of Part 8A(0.270 g, 1.19 mmol) dropwise over 5 min. The resulting mixture warmedslowly to ambient temperature as the cooling bath evaporated overnight.Saturated aqueous NaHCO₃ (50 mL) was then added with transfer to aseparatory funnel and the layers separated. The aqueous layer washedwith CH₂Cl₂ (3×25 mL) and the combined organic layers dried over MgSO₄,filtered and concentrated in vacuo. Subsequent purification bychromatography on silica using 3:1 hexanes/EtOAc afforded the titlecompound as a pale yellow oil (0.115 g, 0.504 mmol; 42.2%).

Part 8C—Preparation of 1-[3-bromo-4-(2-fluoroethyl)phenyl]methanamine

LiAlH₄ (3.79 mmol; 3.79 mL of a 1.0 M solution in THF) was cooled to 0°C. using an ice bath then treated with MeOH (461 μL, 11.4 mmol) dropwiseover 5 min. The product of Part 8B (0.482 mmol; 3.00 mL of a 0.16 Msolution in THF) was then added and the resulting solution warmed slowlyto ambient temperature as the ice bath melted. After 6 h, excess LiAlH₄was consumed by the careful addition of H₂O (0.50 mL). The resultingwhite suspension was successively treated with 15% aqueous NaOH (0.50mL) and H₂O (1.50 mL) and stirred for 15 min to a fine white slurry. Theresulting mixture was filtered through a pad of Celite and concentratedin vacuo. The crude material thus obtained was purified bychromatography on silica using 4:1 CH₂Cl₂/MeOH to afford the titlecompound as a pale yellow oil (11.0 mg, 0.047 mmol; 9.8%).

Part 8D—Preparation of 1-[3-bromo-4-(2-fluoroethyl)benzyl]guanidine,trifluoroacetic acid salt

The product of Part 8C (11.0 mg, 0.047 mmol) was dissolved in MeCN (2.00mL) and successively treated with N,N-diisopropylethylamine (18.2 μL,0.104 mmol) and 1H-pyrazole-1-carboximidamide (15.3 mg, 0.104 mmol) atambient temperature. After 2 h, all volatiles were removed in vacuo andthe residue purified by HPLC on a Phenomenex Luna C18 column (21.2×250mm) using 1%/min gradient from 10-40% MeCN containing 0.1% CF₃CO₂H and10% H₂O at 20 mL/min. The main product peak was collected, pooled andlyophilized to a white solid.

Part 8E—Preparation of 2-[4-(aminomethyl)-2-bromophenyl]ethanol

LiAlH₄ (8.85 mmol; 8.85 mL of a 1.0 M solution in THF) was cooled to 0°C. using an ice bath then treated with MeOH (1.08 mL, 26.4 mmol)dropwise over 5 min. The product of Part 8A (1.11 mmol; 1.00 mL of a1.11 M solution in THF) was then added and the resulting solution warmedslowly to ambient temperature as the ice bath melted. After 4.5 h,excess LiAlH₄ was consumed by the careful addition of H₂O (0.335 mL).The resulting white suspension was successively treated with 15% aqueousNaOH (0.335 mL) and H₂O (1.01 mL) and stirred for 15 min to a fine whiteslurry. The resulting mixture was filtered through a pad of Celite andthe filter cake exhaustively washed with THF and MeOH (3×0.5 mL each).The combined filtrate was concentrated in vacuo to a pale yellow oilthat was used without further purification in the subsequent reaction.

Part 8F—Preparation of tert-butyl[(Z)-[(tert-butoxycarbonyl)amino]{[3-bromo-4-(2-hydroxyethyl)benzyl]amino}methylidene]carbamate

The product of Part 8E (0.162 g, 0.704 mmol) was dissolved in MeCN (1.00mL) and successively treated with N,N-diisopropylethylamine (123 μL,0.705 mmol) and N,N′-di-Boc-1H-pyrazole-1-carboxamidine (0.219 g, 0.705mmol) at ambient temperature. After 0.5 h, all volatiles were removed invacuo and the residue redissolved in CH₂Cl₂ (15 mL) with transfer to aseparatory funnel. The CH₂Cl₂ solution was successively washed with 10%aqueous citric acid, H₂O and saturated aqueous NaCl (1×15 mL each) thendried over Na₂SO₄, filtered and concentrated in vacuo. Subsequentpurification by chromatography on silica, using a hexanes/EtOAc gradientfrom 0-100% EtOAc over 17 min, afforded the title compound as acolorless oil (0.235 g, 0.497 mmol; 70.7%).

Part 8G—Preparation of2-{3-bromo-4-[(N′,N″-bis(tert-butoxycarbonyl)carbamimid-amido)methyl]phenyl}ethyl4-methylbenzenesulfonate

The product of Part 8F (0.220 g, 0.465 mmol) was dissolved in CH₂Cl₂(2.00 mL) and successively treated with p-toluenesulfonyl chloride(0.133 g, 0.698 mmol) and pyridine (83 μL, 1.03 mmol) at 0° C. After 5h, the resulting solution was diluted with CH₂Cl₂ (10 mL) with transferto a separatory funnel. The CH₂Cl₂ solution was successively washed with5% aqueous NaHCO₃, H₂O and saturated aqueous NaCl (1×15 mL each) thendried over Na₂SO₄, filtered and concentrated in vacuo. Subsequentpurification by chromatography on silica, using a hexanes/EtOAc gradientfrom 0-100% EtOAc over 17 min, afforded the title compound as a whitesolid (0.183 g, 0.292 mmol; 62.7%).

Part 8H—Preparation of1-{4-[3-bromo-2-[¹⁸F]fluoroethyl]benzyl}guanidine, formic acid salt

An MP1 anion exchange cartridge containing 1,000 mCi of [¹⁸F]NaF(produced according to the general procedure described in Part 1D) waseluted with 0.20% aqueous K₂CO₃ (1.0 mL), using an automated liquidhandling system, into a 25 mL conical-bottomed silanized flask. Allvolatiles were removed by applying a gentle stream of warm Ar andapplied vacuum. The contents of the flask were reconstituted with 0.5 mLof MeCN, and concentrated again using warm Ar and applied vacuum(azeotropic evaporation). The residue was treated with a solution of4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (21.7 mg) inMeCN (0.90 mL) then transferred to a solution of the product of Part 8G(5.00 mg) in dry DMSO (0.50 mL). The resulting solution was heated to80° C., maintained 30 min then cooled to ambient temperature andconcentrated. The residue thus obtained was redissolved in CF₃CO₂H (1.00mL), stirred 15 min at 40° C. then cooled and concentrated. Subsequentpurification by HPLC on a Phenomenex Luna C18(2) column (250×10 mm, 5micron particle size, 100 Angstrom pore size) using a 5.0%/min gradientof 0-100% MeCN containing 0.1% HCO₂H acid at a flow rate of 2.0 mL/min.The title compound was collected at 14 min, all volatiles removed, andthe residue reconstituted with 10% aqueous ethanol solution forbiological experiments.

Example 11 1-((6-(2-fluoroethoxy)naphthalen-2-yl)methyl)guanidine

Part 11A—Preparation of 6-(2-fluoroethoxy)naphthalene-2-carbonitrile

6-Hydroxynaphthalene-2-carbonitrile (2.00 g, 11.8 mmol) was dissolved inDMSO (36.0 mL) and successively treated with 1-bromo-2-fluoroethane(1.32 mL, 17.7 mmol) and K₂CO₃ (4.90 g, 35.5 mmol) at ambienttemperature. The resulting suspension was stirred 16 h then filteredthrough a scintered glass funnel of medium porosity and treated withEtOAc (150 mL). The EtOAc solution was transferred to a separatoryfunnel where it was successively washed with H₂O (200 mL), 5 N NaOH (50mL) and saturated aqueous NaCl then dried over MgSO₄, filtered andconcentrated in vacuo to a pale yellow solid that was used withoutfurther purification in the subsequent reaction.

Part 11B—Preparation of 1-[6-(2-fluoroethoxy)naphthalen-2-yl]methanamine

The product of Part 11A (0.750 g, 3.49 mmol) was dissolved in Et₂O/THF(1:1 v/v, 24.0 mL), cooled to 0° C. and treated with LiAlH₄ (0.463 g,12.2 mmol) portionwise over 5 min. After 3 h, excess LiAlH₄ was consumedby the careful addition of H₂O (0.463 mL). The resulting whitesuspension was successively treated with 15% aqueous NaOH (0.463 mL) andH₂O (1.39 mL) and stirred for 15 min to a fine white slurry. Theresulting mixture was filtered through a pad of Celite and the filtrateconcentrated in vacuo to a pale yellow solid that was used withoutfurther purification in the subsequent reaction.

Part 11C—Preparation of tert-butyl[(Z)-[(tert-butoxycarbonyl)amino]{[6-(2-fluoroethoxy)naphthalen-2-yl]amino}methylidene]carbamate

The product of Part 11B (0.500 g, 2.28 mmol) was dissolved in MeOH (25.0mL) and successively treated withN,N′-di-Boc-1H-pyrazole-1-carboxamidine (0.849 g, 2.74 mmol) at ambienttemperature. After 2 h, all volatiles were removed in vacuo and theresidue purified by chromatography on silica to afford the titlecompound as a white solid.

Part 11D—Preparation of1-{[6-(2-fluoroethoxy)naphthalen-2-yl]methyl}guanidine, hydrochloricacid salt

The product of Part 11C (75.0 mg, 0.163 mmol) was dissolved in dioxane(1.00 mL) then treated with concentrated HCl (1.50 mL) at ambienttemperature. After 3 h, all volatiles were removed in vacuo, the residueredissolved in H₂O/MeCN (1:1 v/v) then lyophilized to a pale yellowsolid (48.0 mg, 0.161 mmol; >98%).

Part 11E—Preparation of methyl6-((tert-butyldimethylsilyl)oxy)naphthalene-2-carboxylate

Methyl 6-hydroxynaphthalene-2-carboxylate (1.00 g, 4.95 mmol) wasdissolved in DMF (20.0 mL) and successively treated withtert-butyldimethylsilyl chloride (1.11 mL, 7.42 mmol) and imidazole(0.673 g, 9.89 mmol) at ambient temperature. After 16 h, the solutionwas partitioned between EtOAc and H₂O with transfer to a separatoryfunnel. The layers separated and the EtOAc layer washed with H₂O (210mL) and saturated aqueous NaCl (300 mL) then dried over MgSO₄, filteredand concentrated in vacuo to a white solid that was used without furtherpurification in the subsequent reaction.

Part 11F—Preparation of(6-((tert-butyldimethylsilyl)oxy)naphthalen-2-yl)methanol

The product of Part 11E (0.500 g, 1.58 mmol) was dissolved in Et₂O (5.00mL), cooled to 0° C. and treated with LiAlH₄ (0.180 g, 4.74 mmol)portionwise over 5 min. After 10 min, excess LiAlH₄ was consumed by thecareful addition of H₂O. The resulting white suspension was successivelytreated with 15% aqueous NaOH and H₂O and stirred for 15 min to a finewhite slurry. The resulting mixture was filtered through a pad of Celiteand the filtrate concentrated in vacuo to a white solid that was usedwithout further purification in the subsequent reaction.

Part 11G—Preparation of tert-butoxy[(E)-amino{(tert-butoxycarbonyl){[(((6-tert-butyldimethylsilyl)oxy)naphthalen-2-yl)methyl]amino}methylidene]carbamate

The product of Part 11F (0.250 g, 0.870 mmol) was dissolved in THF (5.00mL), successively treated with 1,3-bis(tert-butoxycarbonyl)guanidine(0.451 g, 1.74 mmol) and PPh₃ (0.456 g, 1.74 mmol) then cooled to 0° C.DIAD (336 μL, 1.74 mmol) was then added dropwise over 5 min at the icebath removed. After 4 h, all volatiles were removed and the residuedirectly purified by chromatography on silica using 4:1 hexanes/Et₂O toafford the title compound as a white solid (0.451 mg, 0.851 mmol;97.9%).

Part 11H—Preparation of tert-butoxy[(E)-amino{(tert-butoxycarbonyl)[(6-hydroxynaphthalen-2-yl)methyl]amino}methylidene]carbamate

The product of Part 11G (0.100 g, 0.189 mmol) was dissolved in THF (0.50mL) then treated with tetrabutylammonium fluoride (0.567 mmol; 0.567 mLof a 1.0 M solution in THF) at ambient temperature. After 2 h, allvolatiles were removed and the residue purified by chromatography onsilica using 4:1 hexanes/EtOAc to afford the title compound as a whitesolid (45.0 mg, 0.108 mmol; 57.3%).

Part 11I—Preparation of1-{[6-(2-[F]fluoroethoxy)naphthalen-2-yl]methyl}guanidine, formic acidsalt

The product of Part 1E was transferred to a 5 mL conical-bottomedWheaton™ reaction vial containing the product of Part 11H (4.2 mg),K₂CO₃ (3.6 mg) and anhydrous DMSO (400 μL). The resulting mixture washeated at 80° C. for 45 min then cooled to ambient temperature, treatedwith CF₃CO₂H (1.00 mL) and warmed to 50° C. After 15 min, the resultingmixture was cooled to ambient temperature, concentrated to dryness thenpurified by HPLC on a Phenomenex Luna C18(2) column (10×250 mm, 5 micronparticle size, 100 Angstrom pore size) using a 5.0%/min gradient of0-100% MeCN containing 0.1% HCO₂H acid at a flow rate of 2.0 mL/min. Thetitle compound was collected, all volatiles removed, and the residuereconstituted with 10% aqueous ethanol solution for biologicalexperiments.

Example 12 1-((6-(3-fluoropropoxy)naphthalen-2-yl)methyl)guanidine

Part 12A—Preparation of tert-butoxy[(E)-amino{(tert-butoxycarbonyl){[(6-(3-fluoropropoxy)naphthalen-2-yl)methyl]amino}methylidene]carbamate

The product of Part 11H (75.0 mg, 0.181 mmol) was dissolved in dry DMF(3.00 mL), successively treated with 3-fluoropropyl4-methylbenzenesulfonate (62.8 mg, 0.271 mmol) and K₂CO₃ (99.7 mg, 0.772mmol) then warmed to 50° C. and maintained 48 h. All volatiles wereremoved, and the residue purified by preparative TLC using 4:1pentane/EtOAc for development, to afford the title compound as a whitepowder (36.0 mg, 0.076 mmol; 41.9%).

Part 12B—Preparation of1-{[6-(2-fluoropropoxy)naphthalen-2-yl]methyl}guanidine, trifluoroaceticacid salt

The product of Part 12A (36.0 mg, 0.076 mmol) was dissolved in dioxane(1.00 mL) then treated with concentrated HCl (1.00 mL) at ambienttemperature. After 45 min all volatiles were removed in vacuo, theresidue redissolved in H₂O/MeCN (1:1 v/v, 2.0 mL) then directly purifiedby HPLC on a Phenomenex Luna C18 column (21.2×250 mm) using a 3%/mingradient from 0-90% MeCN containing 0.1% CF₃CO₂H and 10% H₂O at 20mL/min to afford the title compound as a white powder (18.0 mg, 0.046mmol; 61.0%).

Part 12C—Preparation of 2-[¹⁸F]fluoropropyl 4-methylbenzenesulfonate

An MP1 anion exchange cartridge containing 1,000 mCi of [¹⁸F]NaF(produced according to the general procedure described in Part 1D) waseluted with 0.20% aqueous K₂CO₃ (1.0 mL), using an automated liquidhandling system, into a 25 mL conical-bottomed silanized flask. Allvolatiles were removed by applying a gentle stream of warm Ar andapplied vacuum. The contents of the flask were reconstituted with 0.5 mLof MeCN, and concentrated again using warm Ar and applied vacuum(azeotropic evaporation). A separate 5 mL conical-bottomed Wheaton™ vialwas used to prepared a solution of4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (19.3 mg) andpropylene di-(p-toluenesulfonate) (4.0 mg) in MeCN (1.0 mL). Theconstituents of the vial were transferred to the 25 mL flask containing[¹⁸F]KF then positioned inside a microwave cavity (model 520 ResonanceInstruments, Skokie, Ill.) and irradiated for 3 min at 75 watts. Aftercooling, the contents of the microwave reaction vial were filteredthrough an anion exchange resin to remove residual fluoride ion,collected in a 5 mL conical-bottomed Wheaton™ reaction vial and usedwithout further purification in the subsequent reaction.

Part 12D—Preparation of1-{[6-(2-[¹⁸F]fluoropropoxy)naphthalen-2-yl]methyl}guanidine, formicacid salt

The product of Part 12C was transferred to a 5 mL conical-bottomedWheaton™ reaction vial containing the product of Part 11H (4.0 mg),K₂CO₃ (2.8 mg) and anhydrous DMSO (400 μL). The resulting mixture washeated at 80° C. for 30 min then cooled to ambient temperature, treatedwith CF₃CO₂H (1.00 mL) and warmed to 50° C. After 15 min, the resultingmixture was cooled to ambient temperature, concentrated to dryness thenpurified by HPLC on a Phenomenex Luna C18(2) column (10×250 mm, 5 micronparticle size, 100 Angstrom pore size) using a 5.0%/min gradient of0-100% MeCN containing 0.1% HCO₂H acid at a flow rate of 2.0 mL/min. Thetitle compound was collected, all volatiles removed, and the residuereconstituted with 10% aqueous ethanol solution for biologicalexperiments.

Example 21 1-(2-(5-(2-fluoroethoxy)-1H-indol-3-yl)ethyl)guanidine

Part 21A—Preparation of tert-butyl[(Z)-[(tert-butoxycarbonyl)amino]{[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino}methylidene]carbamate

Serotonin hydrochloride (2.00 g, 11.3 mmol) was dissolved in MeCN (38.0mL) and successively treated with N,N-diisopropylethylamine (1.98 mL,11.3 mmol) and N,N′-di-Boc-1H-pyrazole-1-carboxamidine (4.20 g, 13.6mmol) at ambient temperature. After 30 min, the resulting suspension wasfiltered though a scintered glass funnel of medium porosity, thefiltrate diluted with H₂O then transferred to a separatory funnel andwashed with EtOAc. The combined washes were further treated with H₂O andsaturated aqueous NaCl then dried over Na₂SO₄, filtered and concentratedin vacuo. Subsequent purification by chromatography on silica using astep gradient from 3:1 hexanes/EtOAc to 1:1 hexanes/EtOAc afforded thetitle compound as a white solid (2.90 g, 6.93 mmol; 61.0%).

Part 21B—Preparation of tert-butyl[(Z)-[(tert-butoxycarbonyl)amino]{[2-(5-(3-fluoroethoxy)-1H-indol-3-yl)ethyl]amino}methylidene]carbamate

The product of Part 21A (0.400 g, 0.956 mmol) was dissolved in DMF (38.0mL) and successively treated with Cs₂CO₃ (1.60 g, 4.78 mmol) and1-bromo-2-fluoroethane (178 μL, 2.39 mmol) at ambient temperature. Theresulting suspension was warmed to 70° C., maintained 1 h then cooled toambient temperature and partitioned between EtOAc and H₂O. The layersseparated and the EtOAc layer further washed with saturated aqueousNaCl, dried over Na₂SO₄, filtered and concentrated in vacuo. Subsequentpurification by chromatography on silica, using a hexanes/EtOAc gradientfrom 0-100% EtOAc over 15 min, afforded the title compound as a whitesolid (0.176 g, 0.379 mmol; 39.6%).

Part 21C—Preparation of1-(2-(5-(2-fluoroethoxy)-1H-indol-3-yl)ethyl)guanidine, trifluoroaceticacid salt

The product of Part 21B (0.100 g, 0.215 mmol) was dissolved in dioxane(1.00 mL) and treated with concentrated HCl (3.00 mL) at ambienttemperature. After 30 min, all volatiles were removed in vacuo and theresidue directly purified by HPLC on a Phenomenex Luna C18 column(21.2×250 mm) using an 8.3%/min gradient from 0-100% MeCN containing0.1% CF₃CO₂H and 10% H₂O at 20 mL/min. The main product peak wascollected, pooled and lyophilized to a white solid. NOTE: an accurateyield could not be obtained due to the extreme hydroscopicity of theselected salt form.

Part D—Preparation of1-(2-(5-(2-[¹⁸F]fluoroethoxy)-1H-indol-3-yl)ethyl)guanidine, formic acidsalt

The product of Part 1E was transferred to a 5 mL conical-bottomedWheaton™ reaction vial containing the product of Part 21A (3.3 mg),Cs₂CO₃ (13.1 mg) and anhydrous DMF (400 μL). The resulting mixture washeated at 80° C. for 45 min then cooled to ambient temperature andconcentrated in vacuo. The residue was treated with CF₃CO₂H (1.00 mL)then warmed to 40° C. and maintained 20 min. The resulting mixture wascooled to ambient temperature, concentrated to dryness then purified byHPLC on a Phenomenex Luna C18(2) column (10×250 mm, 5 micron particlesize, 100 Angstrom pore size) using a 5.0%/min gradient of 0-100% MeCNcontaining 0.1% HCO₂H acid at a flow rate of 2.0 mL/min. The titlecompound was collected, all volatiles removed, and the residuereconstituted with 10% aqueous ethanol solution for biologicalexperiments.

Example 33 1-(4-(3-fluoropropyl)phenethyl)guanidine

Part 33A—Preparation of [4-(3-hydroxyprop-1-yn-1-yl)phenyl]acetonitrile

(4-Iodophenyl)acetonitrile (1.00 g, 4.12 mmol), PPh₃ (11.0 mg, 0.041mmol) and propargyl alcohol (243 μL, 4.12 mmol) were dissolved inN,N-diethylamine (14.0 mL) then treated with 8.0 mg CuI (0.041 mmol; 1.0mol %) and 11.0 mg PdCl₂ (0.041 mmol; 1.0 mol %) at ambient temperature.After 48 h, all volatiles were removed in vacuo and the residue purifiedby chromatography on silica using a hexanes/EtOAc gradient from 0-100%EtOAc over 18 min to afford the title compound as an orange solid (0.453g, 2.65 mmol; 64.3%).

Part 33B—Preparation of 3-[4-(2-aminoethyl)phenyl]propan-1-ol,hydrochloric acid salt

The product of Part 33A (0.386 g, 2.26 mmol) was dissolved in EtOH (22.0mL) then successively treated with concentrated HCl (3.00 mL) and Pd/C(0.363 mmol; 16 mol %) at ambient temperature. The headspace of thereaction vessel was sparged with 50 psi H₂ then maintained 16 h. Uponcomplete reduction, the headspace was sparged with dry N₂ and thecatalyst removed by filtration through Celite. The filter cake wasexhaustively washed with EtOH and the combined filtrates concentrated invacuo to an orange solid (0.420 g). The crude material was used withoutfurther purification in the subsequent reaction.

Part 33C—Preparation of tert-butoxy{(Z)-({2-[4-(3-hydroxypropyl)phenyl]ethyl}amino)[(tert-butoxycarbonyl)amino]methylidene}carbamate

The product of Part 33B (2.26 mmol theoretical) was dissolved in MeCN(1.00 mL) and successively treated with N,N-diisopropylethylamine (816μL, 4.69 mmol) and N,N′-di-Boc-1H-pyrazole-1-carboxamidine (0.831 g,2.68 mmol) at ambient temperature. After 45 min, the solution wasdiluted with H₂O with transfer to a separatory funnel then washed withEtOAc. The combined EtOAc washes were further washed with H₂O andsaturated aqueous NaCl then dried over Na₂SO₄, filtered and concentratedin vacuo. Subsequent purification by chromatography on silica, using ahexanes/EtOAc gradient from 0-100% EtOAc over 18 min, afforded the titlecompound as a pale yellow solid (0.288 g, 0.683 mmol; 30.3%).

Part 33D—Preparation of tert-butoxy{(Z)-({2-[4-(3-fluoropropyl)phenyl]ethyl}amino)[(tert-butoxycarbonyl)amino]methylidene}carbamate

Deoxo-Fluor® (115 μL, 0.521 mmol) was diluted with CH₂Cl₂ (57 μL) thencooled to 0° C. and treated with a solution of the product of Part 33C(0.474 mmol; 100 μL of 4.74 M solution in CH₂Cl₂) dropwise over 2 min.The resulting mixture warmed slowly to ambient temperature as thecooling bath evaporated overnight. All volatiles were removed in vacuoand the residue directly purified by chromatography on silica using ahexanes/EtOAc gradient from 0-100% EtOAc over 18 min to afford the titlecompound as a white solid (24.5 mg, 0.0578 mmol; 12.2%).

Part 33E—Preparation of 1-(4-(3-fluoropropyl)phenethyl)guanidine,trifluoroacetic acid salt

The product of Part 33D (20.0 mg, 0.047 mmol) was dissolved in dioxane(1.00 mL) then treated with concentrated HCl (3.00 mL) at ambienttemperature. After 30 min all volatiles were removed in vacuo, theresidue redissolved in H₂O/MeCN (1:1 v/v, 2.0 mL) then directly purifiedby HPLC on a Phenomenex Luna C18 column (21.2×250 mm) using a 7.1%/mingradient from 0-100% MeCN containing 0.1% CF₃CO₂H and 10% H₂O at 20mL/min to afford the title compound as a white powder (16.0 mg, 0.047mmol; >98%).

Part 33F—Preparation of3-{4-[2-(N′,N″-bis(tert-butoxycarbonyl)carbamimidamido)ethyl]phenyl}propyl 4-methylbenzenesulfonate

The product of Part 33C (20.0 mg, 0.047 mmol) was dissolved in CH₂Cl₂(336 μL) and successively treated with p-toluenesulfonyl chloride (13.0mg, 0.071 mmol) and pyridine (38 μL, 0.470 mmol) at 0° C. After 16 h,the resulting solution was diluted with CH₂Cl₂, with transfer to aseparatory funnel then successively washed with 5% aqueous CuSO₄, H₂Oand saturated aqueous NaCl. After drying over Na₂SO₄, the solution wasfiltered and concentrated in vacuo then purified by chromatography onsilica, using a hexanes/EtOAc gradient from 0-100% EtOAc over 18 min, toafford the title compound as a colorless oil (5.0 mg, 8.7 μmol; 18.3%).

Part 33G—Preparation of 1-(4-(3-[¹⁸F]fluoropropyl)phenethyl)guanidine,formic acid salt

An MP1 anion exchange cartridge containing 1,000 mCi of [¹⁸F]NaF(produced according to the general procedure described in Part 1D) waseluted with 0.20% aqueous K₂CO₃ (1.0 mL), using an automated liquidhandling system, into a 25 mL conical-bottomed silanized flask. Allvolatiles were removed by applying a gentle stream of warm Ar andapplied vacuum. The contents of the flask were reconstituted with 0.5 mLof MeCN, and concentrated again using warm Ar and applied vacuum(azeotropic evaporation). The residue was treated with a solution of4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (20.0 mg) inMeCN (0.90 mL) then transferred to a solution of the product of Part 33F(4.4 mg) in dry MeCN (0.40 mL). The constituents of the vial were thenpositioned inside a microwave cavity (model 520 Resonance Instruments,Skokie, Ill.) and irradiated for 3 min at 100 watts. The resultingsolution was cooled, treated with CF₃CO₂H (1.00 mL) and the microwaveheating cycle repeated. After cooling, all volatiles were removed andthe residue purified by HPLC on a Phenomenex Luna C18(2) column (250×10mm, 5 micron particle size, 100 Angstrom pore size) using a 5.0%/mingradient of 0-100% MeCN containing 0.1% HCO₂H acid at a flow rate of 2.0mL/min. The title compound was collected, all volatiles removed, and theresidue reconstituted with 10% aqueous ethanol solution for biologicalexperiments.

Example 35 In-Vitro Assays Part 35A—Norepinephrine Transporter BindingAssay

Individual inhibitors were dissolved in incubation buffer (50 mMTris-HCl, 10% sucrose, pH 7.4) at appropriate dilutions. The inhibitorsolutions were added to the wells of a microtiter plate (40 μL/well) intriplicate. Each well of test agent (and appropriate control wells) wastreated with a mixture of MDCK cell membrane preparation (22.4 μg ofmembrane) expressing human norepinephrine transporter (Bmax=3.7 pmolnorepinephrine transporter/mg protein), and [³H]desipramine (2 nM, 64.8Ci/mmol) in a total volume of 0.2 mL. The resulting mixtures wereincubated for 2 h on ice.

A 96 well GF/C filter plate was presoaked with coating buffer (0.5%polyvinylpyrrolidine and 0.1% Tween 20) for 2 h at room temperature,then washed with incubation buffer (6×0.2 mL). The competition reactionswere transferred to the coated plate and filtered. The filter plate waswashed (6×0.2 mL) with ice cold wash buffer (50 mM Tris-HCl, 0.9% NaCl,pH 7.4) then dried overnight and treated with 25 μL scintillation fluidfor analysis on a plate reader (Microbeta TriLux 1450 LSC andLuminescence counter, Perkin Elmer, Shelton Conn.).

Part 35B—Cell Preparation

Rat pheochromocytoma cell line (PC-12) were purchased from the AmericanType Culture Collection (ATCC) then cultured in collagen-coated flasks(BD Bio Coat Collagen Type 1, BD Biosciences) using a growth mediacomposed of F-12 K media, 2 mM L-glutamine, 15% horse serum, 2.5% fetalbovine serum (FBS) and 1% penicillin-streptomycin.

Part 35C—PC-12 Binding Assay

Prepared PC-12 cells were seeded into 6-well plates at a density of1×10⁶ cells/well with 2 mL of growth media and maintained 24 h at 37° C.under a 5% CO₂ atmosphere. The media was exchanged and each well treatedwith 0.1 μCi test agent, with or without 1 μM desipramine. The resultingmixture was incubated for 60 min at 37° C. and 5% CO₂ then centrifugedat 500×g for 3 min and washed with PBS buffer. Radioactivity associatedwith the cells was then measured, and total uptake determined in thewells without desipramine; nonspecific uptake was measured in theassociated wells containing desipramine. The specific NET mediated celluptake is calculated as percent total uptake minus percent nonspecificuptake.

TABLE 1 In-vitro association data PC-12 (% bound) Example NET Affinity(μM) Control Block 1 7.27 3.1 0.30 2 11.19 3.20 0.60 3 7.35 32.76 2.36 45.41 1.00 0.50 5 18.73 1.00 0.90 6 7.91 2.40 0.70 7 10.04 1.40 0.70 817.37 1.30 0.60 9 3.07 3.90 3.30 10 >73.5 — — 11 0.12 23.90 2.70 12 0.145.30 0.50 13 >73.5 — — 14 >73.5 — — 15 32.11 — — 16 >73.5 — — 17 59.19 —— 18 >73.5 — — 19 70.71 — — 20 2.06 0.10 0.10 21 1.19 0.10 0.10 22 18.970.00 0.00 23 6.42 1.40 0.50 24 4.86 2.10 0.90 25 >73.5 — — 26 >73.5 — —27 1.55 — — 28 7.89 0.10 0.10 29 10.30 12.20 2.20 30 2.01 — — 31 12.96 —— 32 115.20 — — 33 3.95 2.30 1.50 34 4.10 — —

Example 36 In Vivo Tissue Distribution Assays Part 36A—AnimalPreparation

Male Sprague Dawley rats (300-500 g, Taconic), and male New Zealandrabbits (3-4 kg, Covance) were used in accordance with our InstitutionalAnimal Care and Use Committee. Rats were anesthetized with sodiumpentobarbital (50 mg/kg, i.p.) and the left femoral vein cannulated withPE50 tubing for drug injection. Rabbits were pre-sedated withacepromazine (0.75 mg/kg i.m.) then anesthetized with ketamine (40mg/kg, i.m.) and xylazine (8 mg/kg, i.m); the marginal ear vein wascannulated for drug injection. Additional doses of anesthetics weregiven as needed.

Part 36B—Tissue Distribution in Rats and Rabbits

After preparation, each animal received a bolus injection of the testagent via the venous catheter. Rats and rabbits were euthanized afterthe injection and samples of the blood, heart, lung, liver, spleen,kidney, femur and muscle were collected. All samples were weighed andcounted for radioactivity (Wallac Wizard 1480, PerkinElmer Life andAnalytical Sciences, Shelton, Conn.); net radioactivity administered ineach animal was determined by subtracting the residual activity in boththe syringe and venous catheter. Tissue uptake of each agent wasdetermined as a percentage of the injected dose per gram tissue (%ID/g).

TABLE 2 In-vivo rat biodistribution data Rat (% ID/g) Example Heart LungLiver Blood 1 1.03 0.24 0.15 0.18 2 1.33 0.94 0.25 0.19 3 0.71 ± 0.241.12 ± 0.29 0.15 ± 0.03 0.35 ± 0.15 4 1.04 ± 0.95 0.34 ± 0.18 0.37 ±0.24 0.13 ± 0.02 5 1.23 0.59 0.26 0.69 7 1.60 ± 0.13 0.80 ± 0.09 0.30 ±0.12 0.11 ± 0.02 8 1.61 0.94 0.27 0.21 11 1.74 ± 0.27 2.71 ± 0.51 0.61 ±0.40 0.51 ± 0.11 12 1.93 ± 0.11 2.09 ± 0.08 0.18 ± 0.01 0.37 ± 0.05 210.35 0.38 1.01 0.41 33 1.94 ± 0.16 0.66 ± 0.11 0.21 ± 0.04 0.10 ± 0.01

TABLE 3 In-vivo rabbit biodistribution data Rabbit (% ID/g) ExampleHeart Lung Liver Blood 3 0.29 0.39 0.02 0.01 4 0.025 0.031 0.012 0.014 70.066 0.078 0.021 0.013 11 0.39 ± 0.02 0.39 ± 0.11 0.02 ± 0.00 0.04 ±0.01 12 0.29 ± 0.09 0.28 ± 0.17 0.02 ± 0.01 0.04 ± 0.02

Example 37 PET Imaging Part 37A—Image Acquisition

Cardiac PET imaging was performed in anesthetized rats and rabbitsprepared according to Part 36A. The animal was appropriately positionedin a microPET camera (Focus220, CTI Molecular Imaging, Inc. Knoxville,Tenn.) for cardiac imaging and the test agent injected using the venouscatheter. Complete acquisition required 120 min.

Part 37B—Image Reconstruction and Analysis

Acquired images were reconstructed in a matrix of 256×256 pixels with 95transverse slices, using the filtered back projection algorithm, anddecay corrected (microPET Manager and ASIPro, CTI Molecular Imaging,Inc. Knoxville, Tenn.); pixel size was 0.47 mm and slice thickness was0.80 mm. Images were reoriented to the cardiac axis and serialtomographic image frames generated for every 10 min interval from 5 to125 minutes. FIGS. 2 through 8 represent images derived using compoundsdescribed herein. FIGS. 2 through 8 represent images derived usingcompounds described herein (e.g., wherein FIG. 2 relates to a compoundfrom Example 1, FIG. 3 relates to a compound from Example 2, etc.).

Example 38

Introduction:

Heart failure (HF) has been associated with increased sympathetic toneand noradrenaline (NA; also referred to herein as NE) release, anddecreased neuronal NA transporter (NAT; also referred herein as NET)function and NA concentration in the failing heart (Rundqvist et al.,Circulation. 1997; 95(1):169-75; Bohm et al., J Am Coll Cardiol. 1995;25(1):146-53; Liang et al., J Clin Invest. 1989; 84(4):1267-75). Thereduced cardiac NA concentration due primarily to the impaired NATfunction is usually referred to as cardiac sympathetic denervation, eventhough the sympathetic activation is elevated with increased NAspillover (Esler, J Appl Physiol. 2010; 108(2):227-37). Cardiacsympathetic neuronal function can be assessed by nuclear imaging.Indeed, global cardiac sympathetic denervation associated with reducedNAT function has been detected by cardiac imaging with a radiolabeledsubstrate for NAT, such as ¹²³I-meta-iodobenzylguanidine (MIBG),¹¹C-meta-hydroxyephedrine (HED) and ¹¹C-epinephrine (Bengel et al., JNucl Cardiol. 2004; 11(5):603-16; Henneman et al., J Nucl Cardiol. 2008;15(3):442-55; Travin, Cardiol Clin. 2009; 27(2):311-27; Carrio, J NuclMed. 2001; 42(7): 1062-76). The imaging findings provided robust valuesin prediction of cardiac events in HF patients (Jacobson et al., J AmColl Cardiol. 2010; 55(20):2212-21; Pietila et al., Eur J Nucl Med.2001; 28(3):373-6). Additionally, incidence of ventricular arrhythmiaand subsequent sudden cardiac death has also been linked to regionalcardiac sympathetic dysfunction (Podrid et al., Circulation. 1990; 82(2Suppl):I103-I113; Chen et al., J Cardiovasc Electrophysiol. 2007;18(1):123-7). Regional cardiac sympathetic denervation (RCSD) orinnervation heterogeneity identified by cardiac imaging with ¹²³I-MIBG,¹¹C-HED or ¹¹C-epinephrine has shown a strong association with enhancedprobability of ventricular arrhythmia both in animals and humans (Dae etal., Circulation. 1997; 96(4):1337-42; Mitrani et al., J Am CollCardiol. 1993; 22(5):1344-53; Sasano et al., J Am Coll Cardiol. 2008;51(23):2266-75; Stevens et al., Circulation. 1998; 98(10):961-8) and acorrelation with arrhythmia induced implantable cardioverterdefibrillator activation or cardiac death in HF patients (Boogers etal., J Am Coll Cardiol. 2010; 55(24):2769-77). However, the imagequality of ¹²³I-MIBG is suboptimal with low energy single-photonemission computed tomography (SPECT) imaging and, in some patients,results in undetected regional defects (Matsunari et al., CircCardiovasc Imaging. 2010; 3(5):595-603). Positron emission tomography(PET) imaging with ¹¹C-HED has demonstrated superiority to ¹²³I-MIBG inimage quality and detection of regional abnormalities (Matsunari et al.,Circ Cardiovasc Imaging. 2010; 3(5):595-603). However, the shorthalf-life of ¹¹C isotope limits its broad clinical application.

Imaging Agent-1 has recently been studied, wherein Imaging Agent-1comprises the structure:

or a pharmaceutically acceptable salt thereof. Imaging Agent-1 it is abenzylguanidine analog and was designed as a NAT substrate forevaluation of cardiac neuronal function. However, Imaging Agent-1 isradiolabeled with ¹⁸F allowing PET imaging and regional radiopharmacyproduction. Imaging with Imaging Agent-1 showed clear detection ofglobal cardiac denervation (Yu et al., Circ Cardiovasc Imaging. 2011;4(4):435-43). In this study, the Imaging Agent-1 imaging profile wasfurther characterized for NAT association in-vitro by comparison withNE, the natural NAT substrate, and MIBG. Given the importance ofregional cardiac denervation in HF stratification, Imaging Agent-1imaging cardiac denervation and heart uptake kinetics in dynamic imagingwere assessed in a rabbit model of RCSD. In addition, RCSD increases therisk of cardiac arrhythmia and treatments with antiarrhythmic drugs,such as dofetilide, may be used in patients with cardiac denervation.Dofetilide is a class III antiarrhythmic agent that selectively blocksthe rapid component of the delayed rectifier outward potassium current(Lenz et al., Pharmacotherapy. 2000; 20(7):776-86). It is generally welltolerated in patients, but torsade de pointes (TdP) may occur followingthe drug induced prolongation of QTc interval. Thus, dofetilide inducedchanges in QTc interval and TdP were investigated in control and RCSDrabbits to determine the potential role of Imaging Agent-1 imagingcardiac sympathetic denervation in antiarrhythmic drug treatment.

Materials and Methods

Cell Uptake Comparison and Competition:

Imaging Agent-1 cell uptake in comparison with ³H-NA and ¹²³I-MIBG wasassayed in human neuroblastoma cells (SK-N-SH, ATCC) with expression ofNAT (Buck et al., Cancer Res. 1985; 45(12 Pt 1):6366-70). Cells wereprepared in 6-well plates at a density of 1×10⁶ cells/well in 2 mLmedia. Imaging Agent-1, ³H-NA or ¹²³I-MIBG at 3.7 kBq was added to eachwell with or without desipramine (1 μM), a selective NAT inhibitor. Inassay with NA, pargyline (10 μM) was included to inhibit monoamineoxidase activity. Following incubation for 60 minutes at 37° C., cellswere washed twice with ice-cold phosphate-buffered saline, trypsinizedand centrifuged at 1000 g for 3 minutes to collect cell pellet.Radioactivity associated with the cells was measured with a γ- (WallacWizard 1480, PerkinElmer) or β-counter (Microbeta TriLux 1450 LSC,PerkinElmer). Each assay was performed in triplicate and the uptake wasexpressed as a percent of total radioactivity added to the well.

For the competitive inhibition assay, Imaging Agent-1 at 3.7 kBq wasincubated in SK-N-SH cells with various concentrations (0.1, 1, 10, or100 βM) of non-radioactive NA, MIBG or ¹⁹F-Imaging Agent-1 (self) at 37°C. for 60 minutes. Similarly, following the incubation, Imaging Agent-1cell uptake was determined. The IC₅₀ value of each agent was determinedusing GraphPad software (v5).

Development of Regional Cardiac Sympathetic Denervation in Rabbits:

Animal study protocol was approved by the Institutional Animal Care andUse Committee. Male New Zealand rabbits (2.5-3.5 kg, Harlan) weremaintained in the AAALAC-accredited Animal Care Facility and acclimatedfor 7 days. The thoracotomy procedure was similar to the methoddescribed previously (Yu et al., J Nucl Cardiol. 2010; 17(4):631-6).Briefly, the rabbit was anesthetized with ketamine (40 mg/kg, im) andxylazine (9 mg/kg, im) and placed in a supine position. Under asepticconditions, a mid-sternotomy was performed carefully to avoid injury ofparietal pleura. The pericardial sac was exposed and incised to revealthe left ventricular (LV) wall. Phenol (89% carbolic acid, Sigma) orsaline (sham-control group) was applied on the surface of the LV lateralwall with a cotton-tipped applicator. The chest was then closed and theanimal allowed to recover.

Cardiac PET Imaging:

Cardiac PET imaging was performed in both sham control and phenolinduced RCSD rabbits at 2 and 12 weeks after surgery. Rabbits wereanesthetized and maintained with isoflurane (0.5-2.5%) using a facemask, and positioned in a microPET camera (Focus220, CTI MolecularImaging, Inc). Approximately 55.5 MBq of Imaging Agent-2, having thestructure:

which is a myocardial perfusion imaging agent (Yu et al., Semin NuclMed. 2011; 41(4):305-13; Yu et al., J Nucl Cardiol. 2007; 14(6):789-98;Nekolla et al., Circulation. 2009; 119(17):2333-42), was injected via acatheter in the marginal ear vein and the heart was imaged for 60minutes. Imaging Agent-1 and Imaging Agent-2 imaging in each rabbit wasperformed in a two-day interval.

Image Reconstruction and Analysis:

Following the acquisition, images were reconstructed in a matrix of256×256 pixels with 95 transverse slices using the OSEM2D algorithm anddecay corrected (microPET Manager and ASIPro, CTI Molecular Imaging,Inc). The pixel size was 0.47 mm and the slice thickness was 0.80 mm.Serial tomographic cardiac images were framed in 2×5-, 2×10-, 3×30-,1×60-, 1×120-, 1×300- and 5×600-second and reoriented based on cardiacaxis. Time activity curves (TAC) were generated from these sequentialimages. The maximal radioactivity in the myocardium was determined fromthe images acquired at 20-30 minutes using Amide software (Amide's aMedical Image Data Examiner, v1.0.1). The normal LV areas of sympatheticinnervation and perfusion (non-defect areas) detected by Imaging Agent-1and Imaging Agent-2 imaging, respectively, were defined as regions withradioactivity ≧50% of the maximal activity. The 50% cutoff was selectedbased on published studies (Matsunari et al., J Nucl Med. 2001;42(10):1579-85; Sherif et al., Circ Cardiovasc Imaging. 2009;2(2):77-84; Simoes et al., Eur Heart J. 2004; 25(7):551-7). In addition,polar map images were generated from reconstructed cardiac short-axisimages using QPS 2008 software (Cedars-Sinai Medical Center).

Assessment of Cardiac Regional Denervation on Dofetilide Treatment:

Dofetilide is an antiarrhythmic drug used clinically and known to causeQTc prolongation and possible TdP. The role of cardiac denervation indofetilide induced changes in QTc interval, premature ventricularcontraction (PVC) and TdP was assessed in sham control and RCSD rabbitsat 3 weeks after surgery. Rabbits were anesthetized with ketamine (40mg/kg, im) and xylazine (9 mg/kg, im), and dofetilide (1 and 4μg/kg/min, Haorui Pharma-Chem Inc. Edison, N.J.) was infused for 10minutes via a catheter in the marginal ear vein. Electrocardiogram (ECG)in lead II configuration was recorded with Ponemah system (v4.3, DataScience International) before and during the drug infusion. Heart rate(HR) and QT interval were derived from ECG waveforms. The QT intervalwas corrected by Fridericia method (QT_(cf)=QT/RR^(1/3)).

Radiopharmaceutical Agents:

Imaging Agent-1 and Imaging Agent-2 were radiosynthesized as previouslydescribed (Yu et al., Circ Cardiovasc Imaging. 2011; 4(4):435-43; Yu etal., J Nucl Cardiol. 2007; 14(6):789-98). The radiochemical purity ofeach imaging agent was consistently >99% and specific activitywas >148000 GBq/mmol. Both agents were formulated in 5% ethanol (v/v)and 50 mg/ml ascorbic acid in water for injection.

Data Analysis:

Values are expressed as mean±SD. Comparisons were performed after datapassed normality and variance homogeneity tests with or without simpledata transformation using SigmaPlot software (v12). One-way ANOVA wasused in comparison of cell uptake of radioactive agents and thenon-defect LV volume detected by cardiac imaging, while two-way repeatedmeasures ANOVA was used in analyzing changes in QT_(cf) interval betweencontrol and denervated rabbits at various time points. The post hoccomparisons were performed with the Bonferroni test. Dofetilide inducedfrequencies of PVC and TdP between control and denervated rabbits werecompared by Fisher Exact Test. p<0.05 was considered statisticallysignificant.

Results:

Comparison of Imaging Agent-1 NAT Association with NA and MIBG:

As shown in FIG. 9, Imaging Agent-1 uptake in SK-N-SH cells was 24.6±9%(n=50), comparable to ¹²³I-MIBG and higher than ³H-NA (n=8/each).Blockade of NAT with desipramine achieved ≧90% inhibition of cell uptakefor Imaging Agent-1 (90±3%), ¹²³I-MIBG (94±2%) and ³H-NA (97±2%).

FIG. 9 shows Imaging Agent-1 uptake (n=50) in comparison with³H-noradrenaline (NA, n=8) and ¹²³I-MIBG (n=8) in SK-N-SH cells with andwithout desipramine to block noradrenaline transporter (NAT). Similarly,NAT blockade inhibited over 90% cell uptake of Imaging Agent-1, NE andMIBG. * indicates p<0.05 vs. control. In competitive inhibition assay(FIG. 10), non-radioactive NA, MIBG and self (n=4/each) inhibitedImaging Agent-1 cell uptake in a concentration-dependent fashion. TheIC₅₀ values were 1.09, 0.21 and 0.90 μM for NA, MIBG and ¹⁹F-ImagingAgent-1, respectively.

FIG. 10 shows dose-response curves of Imaging Agent-1 uptake in SK-N-SHcells in the presence of increasing concentrations of non-radioactivecompounds: noradrenaline (NA, n=4), MIBG (n=4, concentration at 100 μMwas not tested) or ¹⁹F-Imaging Agent-1 (n=4). Results are expressed aspercent of control Imaging Agent-1 uptake at each concentration of thecompound. NA, MIBG and ¹⁹F-Imaging Agent-1 inhibited Imaging Agent-1cell uptake concentration-dependently with IC₅₀ values in a 0.2-1.1 μMrange.

Assessment of Cardiac Denervation by Imaging with Imaging Agent-1 andImaging Agent-2:

Cardiac sympathetic innervation and myocardial perfusion were assessedby imaging with Imaging Agent-1 and Imaging Agent-2, respectively. Incontrol rabbits (n=3-5, FIG. 11), the images of both agents showed welldelineated myocardium with homogeneous activity distribution. Theradioactivity in adjacent organs, like the blood, liver and lung, waslow. In cardiac phenol denervated rabbits (n=8-14, FIG. 12), ImagingAgent-2 imaging showed well perfused myocardium, similar to that in thecontrol. In contrast, in the same rabbit, cardiac neuronal imaging withImaging Agent-1 revealed denervated regions in the LV wall. Thedenervated area was observed in the views of both cardiac short- andlong-axis and polar map. Additionally, the denervated area reduced inImaging Agent-1 images from 2 to 12 weeks after phenol denervation.

FIG. 11 shows representative cardiac images and polar maps of ImagingAgent-1 and Imaging Agent-2, a PET myocardial perfusion imaging agent,from a control rabbit (same rabbit imaged 2 times). The images wereacquired at 20-30 min after injection. The myocardium was clearlydelineated with homogeneous activity distribution in the left ventricle.Radioactivity levels in the adjacent organs were low. FIG. 12 showsrepresentative cardiac images and polar maps of Imaging Agent-1 andImaging Agent-2, a PET myocardial perfusion imaging agent, from aregional cardiac denervated rabbit (same rabbit imaged 3 times). Theimages were acquired at 20-30 min after injection. The regionaldenervation was detected by Imaging Agent-1 imaging at 2 weeks afterphenol denervation and the defect was not due to reduced perfusion(normal Imaging Agent-2 images). The denervated area observed in ImagingAgent-1 images was reduced from 2 to 12 weeks post denervation,indicating re-innervation in the previous denervated area.

As shown in the injected dose corrected TACs (FIG. 13A-FIG. 13C),radioactivity in the blood cleared similarly for Imaging Agent-1 andImaging Agent-2 in control rabbits: reaching a peak immediately after ivadministration, then decreasing rapidly with time. In the heart, theactivity levels for Imaging Agent-1 exhibited a quick washout after theinitial peak and then plateaued (FIG. 13B). This differed from ImagingAgent-2 (FIG. 13A), where the plateau was reached without marked washoutfollowing the initial activity peak in the heart. However, a small andslow decrease in Imaging Agent-2 levels was observed between 5 to 25minutes in the rabbit heart. Radioactivity levels in the liver clearedrapidly after injection of both imaging agents. In RCSD rabbits (FIG.13C), Imaging Agent-1 was delivered to the denervated region initiallyand then washed out to a plateau, lower than that in the innervatedregion.

FIG. 13A-FIG. 13C shows representative time-activity curves (TAC)derived from Imaging Agent-2 and Imaging Agent-1 images in the samecontrol rabbit (FIG. 13A and FIG. 13B) as shown in FIG. 11, and fromImaging Agent-1 images in the denervated rabbit (FIG. 13C) as shown inFIG. 12. Regions of interest were selected from the anterior wall of theLV (heart), liver and LV chamber (blood) in the control rabbit, and fromthe non-defect area of the LV anterior wall (innervated region) and thedefect area (denervated region). TACs were expressed as video intensityunit corrected by injected dose (MBq). For visual simplicity, only TACsof the heart and blood were shown in the first 2 minutes. Unlike ImagingAgent-2 which reached an uptake plateau phase immediately afterinjection, Imaging Agent-1 washed quickly from the heart initially andthem reached a plateau phase. Comparison of non-defect LV Areas detectedby Imaging Agent-1 and Imaging Agent-2: The innervated and perfused LVareas, which were defined as total LV volume with radioactive intensity≧50% of the maximal activity in cardiac images of Imaging Agent-1 andImaging Agent-2, were compared between sham control (n=3-5) and RCSD(n=8-14) rabbits (FIG. 14). The perfused LV region detected by ImagingAgent-2 imaging was 21594±1805 voxels in control rabbits, similar to theperfused area detected in RCSD rabbits. However, Imaging Agent-1 imagingrevealed the denervated region in RCSD rabbits, and the innervated area(non-defect area) decreased by 48% compared to the control at 2 weeks(Early) post cardiac phenol denervation. Following the recovery from 2to 12 weeks (Late), the denervated area recovered partially and theinnervated area increased by 37%, significantly larger than that at 2weeks but still less than in sham control rabbits.

FIG. 14 shows image quantification to assess non-defect left ventricularareas (normal perfused and innervated areas detected by Imaging Agent-2and Imaging Agent-1 imaging respectively) in rabbits of control (n=3-5),and 2 weeks (Early, n=1-14) and 12 weeks (Late, n=8) post denervation.Regional phenol denervation did not impair myocardial perfusion, butreduced the innervated area detected by Imaging Agent-1 at 2 weeks postdenervation. The innervated area increased at 12 weeks, indicatingre-innervation. * indicates p<0.05 vs. control and + indicates p<0.05vs. early time point.

Effect of Regional Cardiac Denervation on Dofetilide Induced ECGChanges:

Changes in ECG induced by iv infusion of dofetilide, an antiarrhythmicdrug, were investigated in sham control (n=6) and RCSD (n=8) rabbits at3 weeks after surgery. ECG waveform was normal with regular cardiacrhythm (FIG. 15A) and baseline values of HR and QT_(cf) were comparable(Table 4) in the two groups before drug infusion. Intravenousadministration of dofetilide induced bradycardia and QT prolongation.Dofetilide induced bradycardia was similar in the two rabbit groups atdoses of both 1 and 4 μg/kg/min (FIG. 15B). In contrast, dofetilide at adose of 4 μg/kg/min increased QT_(cf) interval to a greater extent thanat 1 μg/kg/min, and the QT_(cf) prolongation was significantly moresevere in RCSD rabbits than the control at both dose levels (FIG. 15C).In addition, dofetilide (4 μg/kg/min) induced PVC and TdP, and thefrequency of these events in RCSD rabbits was high, but did not reachstatistical significance compared to the sham control (Table 4).

FIG. 15A shows examples of ECG tracings in rabbits before and duringdofetilide infusion. Before infusion (Control), ECG was normal withregular rhythm. During the infusion, arrhythmia was observed withpremature ventricular contractions (PVC) and torsade de pointes (TdP).FIG. 15B and FIG. 15C show comparison of changes in heart rate (HR) andQT_(cf) interval (corrected by Fridericia method) between sham control(n=6) and regional cardiac denervated (n=8) rabbits iv infused withdofetilide at doses of 1 and 4 μg/kg/min for 10 minutes. Dofetilideinfusion induced bradycardia and QT_(cf) prolongation. In contrast tochanges in HR (similar between control and denervated groups),dofetilide increased QT_(cf) interval more in denervated than in controlrabbits at both doses. Control-D1 and -D4: control rabbits infused withdofetilide at 1 and 4 μg/kg/min; Denervated-D1 and -D4: denervatedrabbits with dofetilide at 1 and 4 μg/kg/min. * indicates p<0.05.

Discussion:

Increased NA release and reduced neuronal NAT function in the heart areassociated with HF. Imaging with a NAT substrate, such as ¹²³I-MIBG or¹¹C-HED, to assess cardiac neuronal function has demonstrated robustvalues in predication of cardiac events and treatment stratification inHF patients (Carrio, J Nucl Med. 2001; 42(7):1062-76; Jacobson et al., JAm Coll Cardiol. 2010; 55(20):2212-21; Pietila et al., Eur J Nucl Med.2001; 28(3):373-6; Boogers et al., J Am Coll Cardiol. 2010;55(24):2769-77). In the present study, the NAT association of ImagingAgent-1, an MIBG analog designed also as a NAT substrate, wasinvestigated in cells with NAT expression. These cells have been usedpreviously for evaluation of MIBG and its analogs (Vaidyanathan et al.,J Nucl Med. 1997; 38(2):330-4; Ko et al., Eur J Nucl Med Mol Imaging.2008; 35(3):554-61). Imaging Agent-1 cell uptake was inhibited bynon-radioactive MIBG, NA or self in a concentration-dependent fashionwith comparable IC₅₀ values in a low μM range, similar to our previouslyreported K_(m) values of ¹⁹F-Imaging Agent-1 and NA (Yu et al., CircCardiovasc Imaging. 2011; 4(4):435-43). Furthermore, blockade of NATwith desipramine reduced the uptake of all these test agents by morethan 90%. These findings suggest that Imaging Agent-1, NA and MIBG sharethe same transporter, NAT, and possess similar NAT association at leastin NAT expressing cells.

Imaging Agent-1 radiolabeled with ¹⁸F is a PET imaging agent. It hasdemonstrated better uptake ratio of the heart to liver and quicker liverclearance than ¹²³I-MIBG in rats and nonhuman primates (NHP) (Yu et al.,Circ Cardiovasc Imaging. 2011; 4(4):435-43). Consistently in this study,cardiac image quality of Imaging Agent-1 was excellent with low activityin adjacent organs (FIG. 11). Immediately after the initial ImagingAgent-1 heart uptake in rabbits, a quick, transit washout phase wasobserved and the retention reached a plateau phase (FIG. 13B). Thiskinetics profile is similar to the observations of Imaging Agent-1 inNHPs (Yu et al., Circ Cardiovasc Imaging. 2011; 4(4):435-43), but seemsto differ from ¹¹C-HED where the cardiac uptake plateaus after theinitial uptake (Raffel et al., J Med Chem. 2007; 50(9):2078-88; Munch etal., Circulation. 2000; 101(5):516-23). This may be due to the uptakekinetics of each imaging agent: integration of various k₁, k₂ and k₃(rate constants for imaging agent distribution into extracellular space,washout from extracellular space back into the blood and transportationinto the neuron via the NAT from the extracellular space, respectively).In a kinetics study comparing phenethylguanidine analogs, Raffel et alsuggested that an analog with rate-limited neuronal uptake (k₃<<k₂,depending more on NAT function) is superior to no rate-limited uptake(k₃>>k₂, depending more on flow, such as Imaging Agent-2 (Nekolla etal., Circulation. 2009; 119(17):2333-42) in evaluation of cardiacneuronal function (Raffel et al., J Med Chem. 2007; 50(9):2078-88). TheTACs generated in rabbits, together with our previous observation inNHPs (high initial cardiac activity followed by a quick washout),support the notion that Imaging Agent-1 cardiac uptake may be ratelimited (k₃<<k₂), depending more on neuronal function than flow.However, based on the instantaneous MIBG heart extraction fractionmeasured within 40 seconds after injection and flow increased byinfusion of dipyridamole in pigs, Glowniak et al demonstrated that MIBGheart uptake is flow dependent (Glowniak et al., J Nucl Med. 1992;33(5):716-23). In contrast to Imaging Agent-1 initial rapid washout,myocardial TACs of Imaging Agent-2 showed a rapid uptake to a plateau(FIG. 13A), supporting the findings that Imaging Agent-2 myocardialuptake may depend on changes in flow at a large range of flow rates (Yuet al., J Nucl Cardiol. 2007; 14(6):789-98; Nekolla et al., Circulation.2009; 119(17):2333-42). A small and slow myocardial Imaging Agent-2washout was seen from 5 to 25 minutes post injection, which differs fromour observations in other species: rats, pigs, NHPs and humans (Yu etal., J Nucl Cardiol. 2007; 14(6):789-98; Nekolla et al., Circulation.2009; 119(17):2333-42; Sherif et al., Circ Cardiovasc Imaging. 2009;2(2):77-84; Maddahi et al., J Nucl Med. 2011; 52(9):1490-8). This couldbe due to species variation.

Moreover, in this study, Imaging Agent-1 imaging demonstrated cleardetection of regional sympathetic denervation in the heart. Animalmodels of sympathetic denervation induced by local phenol application onthe myocardial surface have been widely utilized in assessment ofregional sympathetic denervation previously (Minardo et al.,Circulation. 1988; 78(4):1008-19; Rimoldi et al., Eur J Nucl Med MolImaging. 2007; 34(2):197-205). Imaging with ¹²³I-MIBG or ¹¹C-HEDdetected the denervated area in the heart. This model differs from thecoronary ligation induced myocardial infarction model in that there isminimal flow interruption and regional cardiac retention of an imagingagent is little affected by flow. A similar scenario of regionalsympathetic denervation is seen clinically in patients with non-ischemiccardiomyopathy, such as diabetes (Scholte et al., Eur J Nucl Med MolImaging. 2010; 37(9):1698-705). In agreement with ¹²³I-MIBG and ¹¹C-HED,Imaging Agent-1 imaging identified the denervated region correspondingto the area that phenol had been applied. The reduced local ImagingAgent-1 uptake was not the consequence of myocardial perfusioninterruption as Imaging Agent-2 imaging showed normal uptake in thedenervated area (FIG. 12). Additionally, myocardial TACs in the RCSDrabbit (FIG. 13c ) also confirmed that Imaging Agent-1 was initiallydelivered by blood to the denervated region, similar to the innervatedarea, and then quickly cleared from that region to a lower levelconsistent with reduced NAT function (low k₃) associated with thedenervation. Cardiac imaging detection of regional sympathetic neuronaldysfunction has been suggested to predict ventricular tachycardia,arrhythmia and increased risk of cardiac death (Dae et al., Circulation.1997; 96(4):1337-42; Mitrani et al., J Am Coll Cardiol. 1993;22(5):1344-53; Sasano et al., J Am Coll Cardiol. 2008; 51(23):2266-75;Stevens et al., Circulation. 1998; 98(10):961-8; Boogers et al., J AmColl Cardiol. 2010; 55(24):2769-77; Minardo et al., Circulation. 1988;78(4): 1008-19; Calkins et al., Circulation. 1993; 88(1):172-9).However, clinical assessment of cardiac neuronal function is notperformed routinely. One of the possible reasons may be associated withthe lack of an ideal neuronal imaging agent for tomographic imaging.Cardiac PET neuronal imaging has been shown to be superior to SPECT inimage quality and identification of neuronal abnormalities (Matsunari etal., Circ Cardiovasc Imaging. 2010; 3(5):595-603). Imaging Agent-1 PETimaging showed high image quality and allowed quantification of regionalsympathetic innervation/denervation. The innervated region increasedover time following phenol denervation in the heart (FIGS. 12 and 14),consistent with reinnervation occurring over time (Odaka et al., J NuclMed. 2001; 42(7):1011-6).

Regional denervated myocardium has been suggested to exhibit comparableeffective refractory period (ERP) to normal innervated area butincreased sensitivity to NA induced ERP shortening (Minardo et al.,Circulation. 1988; 78(4):1008-19) or increased ERP but similarsensitivity to NA induced ERP shortening (Calkins et al., Circulation.1993; 88(1):172-9). Regardless of the different findings, heterogeneityof sympathetic innervation may render the heart abnormalelectrophysiologically and increase sensitivity to drugs which interactwith cardiac ion channel conductance, such as antiarrhythmic drugs(Nattel, J Cardiovasc Electrophysiol. 1999; 10(2):272-82). In thisstudy, we observed a marked increase in QTc prolongation in regionalcardiac denervated rabbits during dofetilide infusion, even though thebaseline values of HR and QTc interval were comparable to the shamcontrol. The dose of dofetilide used in this study is in a range ofclinical doses (500 μg twice a day with >90% bioavailability in humans,Package Insert). Dofetilide is known to increases ERP (Lenz et al.,Pharmacotherapy. 2000; 20(7):776-86) and this action seems to bepotentiated by regional denervation or innervation heterogeneity.Similarly, in humans, an antiarrhythmic drug (ibutilide) induced QTprolongation, not changes in HR, was exaggerated when the autonomicsystem was impaired (Smith et al., J Cardiovasc Electrophysiol. 2007;18(9):960-4). These findings suggested that denervation in the heartenhances cardiac risk to some antiarrhythmic drug treatments, and thisrisk associated with innervation dysfunction can potentially be assessedby Imaging Agent-1 imaging.

Conclusion:

Imaging Agent-1 was designed as an ¹⁸F labeled NAT substrate for cardiacsympathetic neuronal imaging. It exhibits high association with NAT andits neuronal uptake may be NAT mediated. Cardiac imaging demonstrateshigh image quality with homogeneous heart uptake and rapid blood andliver clearance in controls, and clear detection and quantification ofregional denervated areas in cardiac denervated animals. Since cardiacdenervation increased the sensitivity to dofetilide inducedelectrophysiological changes, Imaging Agent-1 cardiac imaging mayprovide a means to identify patients with enhanced risk todofetilide-like antiarrhythmic agents.

TABLE 4 Control values and dofetilide induced events in control andregional cardiac denervated rabbits Control value Dofetilide inducedevents (Before dofetilide infusion) (4 μg/kg/min iv infusion) HR(beat/min) QT_(cf) (msec) PVC TdP Sham (n = 6) 158 ± 10 236 ± 5 3 (50%)1 (17%) Denervated 169 ± 7  246 ± 8 5 (63%) 2 (25%) (n = 8) HR: heartrate, QT_(cf): QT interval corrected by Fridericia method, PVC:premature ventricular contraction, TdP: torsade de pointes.

Example 39

The following example describes studies completed on rabbits to assesscardiac perfusion and innervation mismatch following myocardialinfarction. The imaging agent employed for determining innervation wasImaging Agent-1 or a salt thereof. The imaging agent employed forimaging cardiac perfusion was Imaging Agent-2.

In this example, the rabbit model of myocardial infarction (MI)comprises a surgical 30-min left coronary temporary occlusion followedby reperfusion. The rabbits recovered from the surgery.

For cardiac PET imaging with Imaging Agent-1 and Imaging Agent-2, theimaging was performed in a 2-day interval. The MI rabbits were assessedat 4, 13, and 46 weeks post ischemia-reperfusion injury. The innervationdefect (e.g., denervation) was determined from the Imaging Agent-1images whereas that of the perfusion defect was determined from theImaging Agent-2 images. The images were analyzed using the MunichHeart™software package. The defect area is defined as a percentage of leftventricle (% LV) area with radioactivity levels <50% of the maximumradioactivity in the LV.

FIG. 16A shows images of a heart of a control rabbit using both ImagingAgent-1 and Imaging Agent-2. As can be observed in the images, the areasof uptake in the heart of the imaging agents are approximately equal forboth agents. In contrast, FIGS. 16B and 16C shows images of a heart ofrabbits having global denervation and regional denervation,respectively. As can be observed in the images, the areas of uptake ofImaging Agent-1 in the heart is less than the areas of uptake of ImagingAgent-2, indicating a mismatch between innervation and perfusion.

FIG. 17 shows images of a heart of a control rabbit using both ImagingAgent-1 and Imaging Agent-2, as well as the corresponding polar maps. Ascan be observed in the images and the polar maps, the areas of uptake inthe heart of the imaging agents is approximately equal for both agents.FIG. 18A-FIG. 18C show images of a heart of a rabbit 4, 13, and 46 weeksfollowing the ischemia-reperfusion injury using both Imaging Agent-1 andImaging Agent-2, as well as their corresponding polar maps. As can beobserved in the images and the polar maps, the areas of uptake ofImaging Agent-1 in the heart is less than the areas of uptake of ImagingAgent-2, indicating a mismatch between innervation and perfusion. Themismatch decreased with time, indicating reinnervation. FIG. 18D shows aplot of the % LV defect versus time for the images shown in FIG.18A-FIG. 18C. Accordingly, it may be beneficial to evaluate the mismatchat an early time point following acute MI.

Example 40

In imaging, noise filtration (NF) is preferred so that noise does notnegatively impact diagnostic information contained in the image. NF withoptimized filter parameters (OFP) may minimize count-related uncertaintywhile preserving diagnostic information. A method is described using acardiac phantom to determine the OFP for the Phase 3 study of ImagingAgent-2 injection.

Based on Standardized Uptake Values (SUVs) in normal patient myocardium,a cardiac phantom fitted with a 45° defect insert was loaded with 12.3uCi/ml in the myocardium and 3.1 uCi/ml in the defect to simulate a 70kg patient injected with midpoint doses for imaging at rest of 2.75 mCi,during pharmacological stress of 6.25 mCi, and during exercise stress of9.25 mCi. A GE Discovery ST PET/CT was then employed to scan the phantomin both 3D and 2D modes. Multiple PET image data sets were firstreconstructed from the listmode rebinning to generate realistic 3Dperfusion images (3D-PI) and 2D ECG-gated images (2D-GI), then filteredwith a 3D Gaussian filter (FWHM=4-20 mm). Defect contrast (DC) was thencalculated to determine OFP for 3D-PI with <5% DC degradation. Leftventricular volume (LVV) was quantified with the QGS cardiac tool todetermine OFP for 2D-GI while maintaining >90% accuracy of LVV. Thesignal-to-noise (SNR), as the mean/SD in normal myocardium was assessedwith respect to the degree of filtering. Finally, in order to test OFPadequacy in a clinical setting, 10 patient images generated on a GEDiscovery ST PET/CT were processed with the appropriate OFP value thenvisually assessed using an image quality score (IQS) (excellent=3,good=2, fair=1, poor=0). The imaging parameters applied are set forth inTable 5 and the results presented in Table 6.

TABLE 5 Imaging Parameters Pharmaco- Rest logical Exercise NormalMyocardial 4.8 11.1 6.7 SUV from Phase II Mean Phase III 2.75 (2.5-3.0)6.25 (6.0-6.5) 9.25 (9.0-9.5) Dose (mCi) Assumed Patient 70 70 70 Weight(kg) F18 Activity 0.184 0.984 0.880 Concentration in Myocardial Wall(uCi/ml) Defect Severity 75% 75% 75% Imaging Duration for 600 600 600 3DPerfusion (sec) Imaging Duration for 600 600 600 2D Gated (sec)

TABLE 6 Results FWHM (mm), DC Degradation FWHM (mm), LVV Accuracy (%),SNR (%) Rest 4, 6, 8, 10, 12, 15, 20,  4,  6,  8, 10, 12, 15, 20, 1.6,3.1, 4.9,  7.8, 11.7, 19.1, 33.2, 50 55 65 70 78.3 93.3 65.2 7.25 7.88.0  8.2  8.2  8.0  7.5 Pharm 4, 6, 8, 10, 12, 15, 20,  4,  6,  8, 10,12, 15, 20, 3.1, 3.1, 4.4,  7.1, 11.1, 18.8, 33.0, 66.7 71.7 76.7 83.393.3 91.7 74.3 8.1 8.3 8.5  8.8  8.7  8.4  7.6 Exercise 4, 6, 8, 10, 12,15, 20,  4,  6,  8, 10, 12, 15, 20, 0.4, 2.7, 3.2,  7.2, 12.2, 21 .1,35.7, 65.1 72.2 77.1 84.2 92.7 91.2 72.5 8.1 8.3 8.5  8.7  8.6  8.3  7.6

Using preferred SNR and DC degradation (<5%) settings, the optimalfilter parameters (OFP) for rest, and pharmacological and exerciseinduced stress 3D perfusion imaging, were found to be FWHM=8.0 mm, whilethe OFP for rest and pharmacological and exercise inducedstress 2D gatedimaging were found to be 15.0 mm and 12.0 mm, respectively. The mean IQSfor the 3D erfusion images were 2.6±0.7 while that for the 2D gatedimages were 2.2±0.6 (data not shown).

A cardiac phantom simulation using known patient myocardial SUVs is aneffective method to determine an optimal noise filter parameter set thatcan produce high-quality diagnostic images when using an Imaging Agent-2injection.

Terms and Equivalents

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the invention maybe practiced otherwise than as specifically described and claimed. Thepresent invention is directed to each individual feature, system,article, material, kit, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,kits, and/or methods, if such features, systems, articles, materials,kits, and/or methods are not mutually inconsistent, is included withinthe scope of the present invention.

The indefinite articles “a” and “an,” as used herein in thespecification and in the claims, unless clearly indicated to thecontrary, should be understood to mean “at least one.”

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Other elements may optionallybe present other than the elements specifically identified by the“and/or” clause, whether related or unrelated to those elementsspecifically identified unless clearly indicated to the contrary. Thus,as a non-limiting example, a reference to “A and/or B,” when used inconjunction with open-ended language such as “comprising” can refer, inone embodiment, to A without B (optionally including elements other thanB); in another embodiment, to B without A (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (i.e. “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.” “Consisting essentially of,” when used in the claims,shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from any one or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” and the like are to be understoodto be open-ended, i.e., to mean including but not limited to. Only thetransitional phrases “consisting of” and “consisting essentially of”shall be closed or semi-closed transitional phrases, respectively, asset forth in the United States Patent Office Manual of Patent ExaminingProcedures, Section 2111.03.

1. A compound of the formula:R⁰—Ar-L-R¹ wherein Ar is substituted or unsubstituted, monocyclic orbicyclic aryl or substituted or unsubstituted, monocyclic or bicyclicheteroaryl; L is a bond; substituted or unsubstituted, cyclic or acyclicalkylene; substituted or unsubstituted, cyclic or acyclic alkenylene;substituted or unsubstituted, cyclic or acyclic alkynylene; orsubstituted or unsubstituted, cyclic or acyclic heteroaliphatic; R¹ is asubstituted or unsubstituted nitrogen-containing moiety; and R⁰ ishalogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, —OR^(A1), —N(R^(A2))₂, —SR^(A1),—C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A2))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂,—NR^(A2)C(═O)R^(A2), —NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1),—NR^(A2)C(═O)N(R^(A2))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A2))₂, —C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1),—C(═NR^(A2))SR^(A1), —C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1),—OC(═NR^(A2))OR^(A1), —OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂ eachoccurrence of R^(A1) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl; andeach occurrence of R^(A2) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, or an amino protecting group, or two R^(A2)groups are joined to form an optionally substituted heterocyclic ring;and R⁰ or R¹ is substituted with an imaging moiety selected from thegroup consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I, or is associated with animaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator, or is an imaging moiety selectedfrom the group consisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I; or a saltthereof; provided the compound is not of the formula

2-124. (canceled)
 125. A compound of the formula:

wherein L is a bond; substituted or unsubstituted, cyclic or acyclicalkylene; substituted or unsubstituted, cyclic or acyclic alkenylene;substituted or unsubstituted, cyclic or acyclic alkynylene; orsubstituted or unsubstituted, cyclic or acyclic heteroaliphatic; R¹ isselected from the group consisting of:

each occurrence of R^(B) is independently hydrogen, substituted orunsubstituted alkyl, or a nitrogen-protecting group, provided at leasttwo R^(B) are hydrogen; R² and R⁶ are hydrogen; each of R³, R⁴ and R⁵ isindependently hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,—OR^(A1), —N(R^(A2))₂, —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1),—C(═O)SR^(A1), —C(═O)N(R^(A2))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1),—OC(═O)SR^(A1), —OC(═O)N(R^(A2))₂, —NR^(A2)C(═O)R^(A2),—NR^(A2)C(═O)OR^(A1), —NR^(A2)C(═O)SR^(A1), —NR^(A2)C(═O)N(R^(A2))₂,—SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A2))₂,—C(═NR^(A2))R^(A1), —C(═NR^(A2))OR^(A1), —C(═NR^(A2))SR^(A1),—C(═NR^(A2))N(R^(A2))₂, —OC(═NR^(A2))R^(A1), —OC(═NR^(A2))OR^(A1),—OC(═NR^(A2))SR^(A1), —OC(═NR^(A2))N(R^(A2))₂,—NR^(A2)C(═NR^(A2))R^(A2), —NR^(A2)C(═NR^(A2))OR^(A1),—NR^(A2)C(═NR^(A2))SR^(A1), —NR^(A2)C(═NR^(A2))N(R^(A2))₂,—SC(═NR^(A2))R^(A1), —SC(═NR^(A2))OR^(A1), —SC(═NR^(A2))SR^(A1),—SC(═NR^(A2))N(R^(A2))₂, —C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1),—C(═S)N(R^(A2))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A2))₂, —NR^(A2)C(═S)R^(A2), —NR^(A2)C(═S)OR^(A1),—NR^(A2)C(═S)SR^(A1), —NR^(A2)C(═S)N(R^(A2))₂, —SC(═S)R^(A1),—SC(═S)OR^(A1), —SC(═S)SR^(A1), —SC(═S)N(R^(A2))₂, —S(═O)R^(A1),—SO₂R^(A1), —NR^(A2)SO₂R^(A1), —SO₂N(R^(A2))₂, —CN, —SCN, or —NO₂; orany two adjacent R³, R⁴ and R⁵ are joined to form an optionallysubstituted or unsubstituted carbocyclic, heterocyclic, aryl, orheteroaryl ring; each occurrence of R^(A1) is independently hydrogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and each occurrence of R^(A2) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or an amino protecting group, or twoR^(A2) groups are joined to form an optionally substituted heterocyclicring; and wherein R⁴ is substituted with an imaging moiety selected fromthe group consisting of ¹⁸F, ⁷⁶Br, and ¹²⁴I; or is associated with animaging moiety selected from the group consisting of ⁶⁴Cu, ⁸⁹Zr,^(99m)Tc, and ¹¹¹In through a chelator; or is ¹²⁴I; or a salt thereofwith the proviso that if one of R³ or R⁵ is Cl, Br, or CF₃, then theother of R³ or R⁵ is not H; and provided the compound is not of theformula:


126. A compound of claim 125, where R¹ is


127. A compound of claim 125, wherein R¹ is

wherein each occurrence of R^(B) is independently hydrogen, substitutedor unsubstituted alkyl, or a nitrogen-protecting group, provided atleast two R^(B) are hydrogen.
 128. A compound of claim 125, wherein R¹is

wherein R^(B) is hydrogen, substituted or unsubstituted alkyl, or anitrogen-protecting group.
 129. A compound of claim 125, wherein R¹ is


130. A compound of claim 125, wherein R¹ is

wherein each occurrence of R^(B) is independently hydrogen, substitutedor unsubstituted alkyl, or a nitrogen-protecting group, provided atleast two R^(B) are hydrogen.
 131. A compound of claim 125, wherein R¹is

wherein R^(B) is hydrogen, substituted or unsubstituted alkyl, or anitrogen-protecting group.
 132. A compound of claim 125, wherein R¹ is


133. A compound of claim 125, wherein R¹ is


134. A compound of claim 125, where R⁴ is

135-281. (canceled)
 282. A compound of the formula:

wherein R⁹ and R¹⁰ are independently selected from the group consistingof H, —OR¹¹, F, Cl, Br, I, —CF₃, alkyl(C₁-C₄), and imaging moiety(I_(m)); R¹¹, R¹² and R¹³ are selected from the group consisting of H,alkyl, and aryl; and W and X are independently selected from the groupconsisting of H, —OR₄, —N(R¹¹)₂, F, Cl, Br, —CF₃, I_(m), aryl, andheteroaryl; wherein A) Y and Z are independently selected from the groupconsisting of —CH—, —CH₂—, —O—, —N—, —NR¹¹—, and —CH═CH— when a linkinggroup Q between Y and Z is present or absent, wherein Q is selected fromthe group consisting of —CH—, —CH₂—, —CR¹¹—, —N—, —NH—, —NR¹¹—, —O—, and—S—; or B) Y and Z are independently selected from the group consistingof H, —OR₄, —N(R¹¹)₂, F, Cl, Br, —CF₃, I_(m), aryl, and heteroaryl whenlinking group Q is absent; wherein I_(m) is selected from the groupconsisting of ¹⁸F, ⁷⁶Br, ¹²⁴I, and ¹³¹I, and is present in either W—Z orR⁹-R¹³; provided the compound is not of the formula:

283-284. (canceled)
 285. A compound of formula:

or a salt thereof.
 286. A pharmaceutical composition comprising acompound of claim 285, or a salt thereof, and optionally apharmaceutically acceptable excipient.
 287. (canceled)
 288. A method ofimaging cardiac innervation comprising steps of: administering aneffective amount of a compound of claim 285 or a salt thereof to asubject; detecting radiation emitted by the compound; and forming animage therefrom.
 289. A method of imaging a subject comprising:administering a compound of claim 285 or a salt thereof; and acquiringat least one image of a portion of the subject.
 290. A method ofdetecting norepinephrine transporter (NET) in a portion of a subject,the method comprising: administering a compound of claim 285 or a saltthereof; and acquiring at least one image of the portion of the subject,wherein the image detects NET in the subject.
 291. A method of selectingan antiarrhythmic agent and/or determining the dose of an antiarrhythmicagent for administration to a subject, the method comprisingadministering to the subject the compound of claim 285 or a saltthereof; acquiring at least one image of a portion of the subject;selecting the antiarrhythmic agent and/or determining the dose of anantiarrhythmic agent for administration to a subject based on the atleast one first image. 292-296. (canceled)
 297. The method of claim 291,wherein a reduced dose of an antiarrhythmic agent that induceselectrophysiological changes in a subject's heart is prescribed based onthe at least one first image indicating presence of cardiac denervation.298. A method comprising administering to the subject the compound ofclaim 285; or a salt thereof; acquiring at least one image of a portionof the subject; and identifying (i) a subject to be treated with anantiarrhythmic agent that does not induce electrophysiological changesin the heart of the subject based on presence of cardiac denervation inthe image, (ii) a subject to be treated with a reduced dose of anantiarrhythmic agent that induces electrophysiological changes in theheart of the subject based on presence of cardiac denervation in theimage, and/or (iii) a subject in need of a dose reduction of anantiarrhythmic agent that induces electrophysiological changes in theheart of the subject based on presence of cardiac denervation in theimage. 299-373. (canceled)